Bicyclic-fused heteroaryl or aryl compounds

ABSTRACT

Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula Ia,as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

FIELD OF THE INVENTION

This invention pertains to compounds useful for the treatment ofautoimmune and inflammatory diseases associated with Interleukin-1Receptor Associated Kinase (IRAK) and more particularly compounds thatmodulate the function of IRAK4.

BACKGROUND OF THE INVENTION

Protein kinases are families of enzymes that catalyze thephosphorylation of specific residues in proteins, broadly classified intyrosine and serine/threonine kinases. Inappropriate activity arisingfrom dysregulation of certain kinases by a variety of mechanisms isbelieved to underlie the causes of many diseases, including but notlimited to, cancer, cardiovascular diseases, allergies, asthma,respiratory diseases, autoimmune diseases, inflammatory diseases, bonediseases, metabolic disorders, and neurological and neurodegenerativediseases. As such, potent and selective inhibitors of kinases are soughtas potential treatments for a variety of human diseases.

There is considerable interest in targeting the innate immune system inthe treatment of autoimmune diseases and sterile inflammation. Receptorsof the innate immune system provide the first line of defense againstbacterial and viral insults. These receptors recognize bacterial andviral products as well as pro-inflammatory cytokines and therebyinitiate a signaling cascade that ultimately results in theup-regulation of inflammatory cytokines such as TNFα, IL6, andinterferons. Recently it has become apparent that self-generated ligandssuch as nucleic acids and products of inflammation such as high-mobilitygroup protein B1 (HMGB1) and Advanced Glycated End-products (AGE) areligands for Toll-like receptors (TLRs) which are key receptors of theinnate immune system (O'Neill 2003, Kanzler et al 2007, Wagner 2006).This demonstrates the role of TLRs in the initiation and perpetuation ofinflammation due to autoimmunity.

Interleukin-1 receptor associated kinase 4 (IRAK4) is a ubiquitouslyexpressed serine/threonine kinase involved in the regulation of innateimmunity (Suzuki & Saito 2006). IRAK4 is responsible for initiatingsignaling from TLRs and members of the IL-1/18 receptor family.Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice werereported to cause reductions in TLR and IL-1 induced pro-inflammatorycytokines (Kawagoe et al 2007; Fraczek et al. 2008; Kim et al. 2007).IRAK4 kinase-dead knock-in mice have also been shown to be resistant toinduced joint inflammation in the antigen-induced-arthritis (AIA) andserum transfer-induced (K/B×N) arthritis models (Koziczak-Holbro 2009).Likewise, humans deficient in IRAK4 also appear to display the inabilityto respond to challenge by Toll ligands and IL-1 (Hernandez & Bastian2006). However, the immunodeficient phenotype of IRAK4-null individualsis narrowly restricted to challenge by gram positive bacteria, but notgram negative bacteria, viruses or fungi. This gram positive sensitivityalso lessens with age, implying redundant or compensating mechanisms forinnate immunity in the absence of IRAK4 (Lavine et al 2007).

These data indicate that inhibitors of IRAK4 kinase activity should havetherapeutic value in treating cytokine driven autoimmune diseases whilehaving minimal immunosuppressive side effects. Additional recent studiessuggest that targeting IRAK4 may be useful in other inflammatorypathologies such as atherosclerosis and diffuse large B-cell lymphoma(Rekhter et al 2008; Ngo et al 2011). Therefore, inhibitors of IRAK4kinase activity are potential therapeutics for a wide variety ofdiseases including but not limited to autoimmunity, inflammation,cardiovascular diseases, cancer, and metabolic diseases. See thefollowing references for additional information: N. Suzuki and T. Saito,Trends in Immunology, 2006, 27, 566. T. Kawagoe, S. Sato, A. Jung, M.Yamamoto, K. Matsui, H. Kato, S. Uematsu, O. Takeuchi and S. Akira,Journal of Experimental Medicine, 2007, 204, 1013. J. Fraczek, T. W.Kim, H. Xiao, J. Yao, Q. Wen, Y. Li, J.-L. Casanova, J. Pryjma and X.Li, Journal of Biological Chemistry, 2008, 283, 31697. T. W. Kim, K.Staschke, K. Bulek, J. Yao, K. Peters, K.-H. Oh, Y. Vandenburg, H. Xiao,W. Qian, T. Hamilton, B. Min, G. Sen, R. Gilmour and X. Li, Journal ofExperimental Medicine, 2007, 204, 1025. M. Koziczak-Holbro, A.Littlewood-Evans, B. Pollinger, J. Kovarik, J. Dawson, G. Zenke, C.Burkhart, M. Muller and H. Gram, Arthritis & Rheumatism, 2009, 60, 1661.M. Hernandez and J. F. Bastian, Current Allergy and Asthma Reports,2006, 6, 468. E. Lavine, R. Somech, J. Y. Zhang, A. Puel, X. Bossuyt, C.Picard, J. L. Casanova and C. M. Roifman, Journal of Allergy andClinical Immunology, 2007, 120, 948. M. Rekhter, K. Staschke, T.Estridge, P. Rutherford, N. Jackson, D. Gifford-Moore, P. Foxworthy, C.Reidy, X.-d. Huang, M. Kalbfleisch, K. Hui, M.-S. Kuo, R. Gilmour and C.J. Vlahos, Biochemical and Biophysical Research Communications, 2008,367, 642. O'Neill, L. A. (2003). “Therapeutic targeting of Toll-likereceptors for inflammatory and infectious diseases.” Curr Opin Pharmacol3(4): 396. Kanzler, H et al. (2007) “Therapeutic targeting of innateimmunity with toll-like receptor agonists and antagonists.” NatureMedicine 13:552. Wagner, H. (2006) “Endogenous TLR ligands andautoimmunity” Advances in Immunol 91: 159. Ngo, V. N. et al. (2011)“Oncogenically active MyD88 mutations in human lymphoma” Nature 470:115.

SUMMARY OF THE INVENTION

The invention provides for compounds of the Formula Ia,

wherein

X and X′ are each independently CR⁸, N or —N⁺—O⁻; Y is independently N,—N⁺—O⁻ or CR^(8′); provided that at least one of X, X′ or Y is neither Nnor —N⁺—O⁻ and that no more than one of X, X′ or Y is —N⁺—O⁻;

R¹ is C₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl; —(CR^(3a)R^(3b))_(m)-(3-to 7-membered cycloalkyl); —(CR^(3a)R^(3b))_(m)-(3- to 7-memberedheterocycloalkyl) having one to three heteroatoms;—(CR^(3a)R^(3b))_(m)-(5- to 10-membered heteroaryl), having one to threeheteroatoms; or —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl; wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl isoptionally substituted with one to five halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b) cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or —C₁-C₆alkoxy;

R² is —(CR^(3a)R^(3b))_(m)-(3- to 10-membered cycloalkyl);—(CR^(3a)R^(3b))_(m)-(3- to 10-membered heterocycloalkyl) having one tothree heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to 10 membered heteroaryl)having one to three heteroatoms; or —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl;wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl isoptionally substituted with one to five R⁴; and wherein, if theheteroatom on said heterocycloalkyl and heteroaryl is N, said N isoptionally substituted with R^(4′); or R² is C₁-C₆alkyl, wherein saidalkyl is optionally substituted with NH₂, OH or cyano;

R^(3a) and R^(3b) for each occurrence are independently hydrogen orC₁-C₃alkyl;

R⁴ for each occurrence is independently a bond, deuterium, halogen,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵, —S(O)R⁹, —S(O)₂R⁹,—NR^(11a)R^(11b), —C(O)R¹⁰, —(CR^(3a)R^(3b)), (3- to 7-memberedcycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl),having one to three heteroatoms, —(CR^(3a)R^(3b))_(n)-(5- to 10 memberedheteroaryl), having one to three heteroatoms, or —(CR^(3a)R^(3b)),—C₆-C₁₂aryl wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroarylor aryl is each optionally and independently substituted with one tofive deuterium, halogen, OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl,C₃-C₆cycloalkyl or C₁-C₆alkoxy; or two R⁴ taken together with therespective carbons to which each are bonded form a 3- to 6-memberedcycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkylor heterocycloalkyl is optionally substituted with one to three halogen,deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano or C₁-C₆alkyl orC₁-C₆alkoxy, wherein the alkyl or alkoxy is optionally substituted withhalogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b) or cyano; and wherein,if a heteroatom on said heterocycloalkyl is N, said N is optionallysubstituted with R^(4′);

R^(4′) is independently C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁰, —S(O)₂R⁹,—(CR^(3a)R^(3b))_(n)-(3- to 7-membered cycloalkyl),—(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl) orC(O)(CH₂)_(t)CN; wherein said alkyl, alkenyl, cycloalkyl, orheterocycloalkyl is each optionally and independently substituted withone to five deuterium, halogen, OH, cyano or C₁-C₆alkoxy; or R⁴ andR^(4′) taken together with the respective atoms to which each are bondedform a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl,wherein said cycloalkyl or heterocycloalkyl is optionally substitutedwith one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy isoptionally substituted with halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b), or cyano;

R⁵ is independently hydrogen or C₁-C₆alkyl, wherein said alkyl isoptionally substituted with halogen, deuterium, C₁-C₆alkoxy,C₁-C₆alkylthiolyl, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl orC₃-C₆cycloalkyl; or two R⁵ taken together with the oxygen atoms to whichthey are bonded form a 5- or 6-membered heterocycloalkyl;

R⁶ is —C(O)NHR⁷, CO₂R⁷ or cyano;

R⁷ is hydrogen or C₁-C₆alkyl;

each R⁸ is independently hydrogen, halogen, cyano, —OR⁵, —SR⁵,—NR^(11a)R^(11b), C₁-C₆alkyl, C₃-C₆cycloalkyl, 3- to 10-memberedheterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein saidalkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionallysubstituted with one to three halogen, —NR^(11a)R^(11b), —OR⁵, —SR⁵,cyano, C₁-C₃ alkyl, —C(O)R¹⁰ or oxo;

R^(8′) is hydrogen, deuterium, halogen, cyano, —OR⁵, —SR⁵ orNR^(11a)NR^(11b);

R⁹ is —(CR^(3a)R^(3b))_(p)—(C₁-C₃alkyl), —(CR^(3a)R^(3b))_(p)-(4- to6-membered cycloalkyl), —(CR^(3a)R^(3b))_(p)-(4- to 6-memberedheterocycloalkyl) or —(CR^(3a)R^(3b))_(p)—(C₅-C₉aryl), wherein saidalkyl, cycloalkyl, heterocycloalkyl or aryl is each optionallysubstituted with fluoro or C₁.C₃alkyl;

R¹⁰ is C₁-C₆alkyl, wherein said alkyl is optionally substituted withdeuterium, halogen, OH, C₁-C₆alkoxy or cyano;

R^(11a) and R^(11b) are each independently hydrogen or C₁-C₆alkyl,wherein said alkyl is optionally substituted with deuterium, C₁-C₆alkoxyor cyano; and if C₂-C₆alkyl, said alkyl is optionally substituted withdeuterium, C₁-C₆alkoxy, cyano, halogen or OH;

m is independently 0, 1, 2 or 3;

n is independently 0, 1, 2 or 3;

p is independently 0 or 1; and

t is 1, 2 or 3;

or a pharmaceutically acceptable salt of said compound or a tautomer ofsaid compound or said salt.

The invention also provides for pharmaceutical compositions comprisingthe compounds, methods of using the compounds, combination therapiesutilizing the compounds and other therapeutic agents and methods ofpreparing the compounds. The invention also provides for intermediatesuseful in the preparation of the compounds of the invention.

In particular, novel bicyclic kinase enzyme inhibitor compounds ofFormula I of the present invention possess a therapeutic role ofinhibiting IRAK4 useful in the area of diseases and/or disorders thatinclude, but are not limited to, cancers, allergic diseases, autoimmunediseases, inflammatory diseases and/or disorders and/or conditionsassociated with inflammation and pain, proliferative diseases,hematopoietic disorders, hematological malignancies, bone disorders,renal disease, fibrosis diseases and/or disorders, metabolic disorders,muscle diseases and/or disorders, respiratory diseases, pulmonarydisorders, genetic development diseases, neurological andneurodegenerative diseases and/or disorders, chronic inflammatorydemyelinating neuropathies, cardiovascular, vascular or heart diseases,ophthalmic/ocular diseases, wound repair, infection and viral diseases.Therefore, inhibition of IRAK4 would have the potential for multipletherapeutic indications over a wide range of unmet needs.

DESCRIPTION OF FIGURES

FIG. 1 : Mean change in ear swelling (μm) from baseline ear measurementson day 5. Mice treated with Example 296 (PO BID daily×5 days) and P40 Ab(IP day 1, 4) had significantly reduced ear swelling on the final daycompared to Vehicle (p value and %).

FIG. 2 : FIG. 2 . Delta paw volume in rat collagen-induced arthritismodel using Example 26.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of exemplary embodiments of the inventionand the examples included therein. It is to be understood that thisinvention is not limited to specific methods of synthesis, which may ofcourse vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

All patents, patent applications and references referred to herein arehereby incorporated by reference in their entirety.

Other features and advantages of this invention will be apparent fromthis specification and the appendent claims which describe theinvention. There are many features of this invention that are notnecessarily fully captured by the claims. It is understood, however,that all such novel subject matter is part of the invention.

Definitions

Unless otherwise defined herein, scientific and technical terms used inconnection with the present invention have the meaning commonlyunderstood by those of ordinary skill in the art. As used in thespecification and the appended claims, the singular forms “a”, “an”, and“the” include plural referents unless the context clearly dictatesotherwise.

The term “about” refers to a relative term denoting an approximation ofplus or minus 10% of the nominal value it refers, in one embodiment, toplus or minus 5%, in another embodiment, to plus or minus 2%. For thefield of this disclosure, this level of approximation is appropriateunless the value is specifically stated require a tighter range.

The term “alkyl” refers to a linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms. In oneembodiment from one to six carbon atoms; and in another embodiment fromone to four carbon atoms; and in another embodiment one to three carbonatoms. Non-limiting examples of such substituents include methyl, ethyl,propyl (including n-propyl and isopropyl), butyl (including n-butyl,isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl and thelike. As appropriate, an alkyl may be optionally substituted at eachcarbon as defined in the claims. Typical substitution includes, but isnot limited to, fluoro, chloro, OH, cyano, alkyl (optionallysubstituted), cycloalkyl and the like.

In some instances, the number of carbon atoms in a hydrocarbonsubstituent (i.e., alkyl, cycloalkyl, etc.) is indicated by the prefix“C_(x)-C_(y)-” or “C_(x-y)”, wherein x is the minimum and y is themaximum number of carbon atoms in the substituent. Thus, for example,“C₁-C₆-alkyl” or “C₁₋₆ alkyl” refers to an alkyl substituent containingfrom 1 to 6 carbon atoms. Illustrating further, C₃-C₆-cycloalkyl orC₃₋₆-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6carbon ring atoms.

Unless otherwise indicated, “alkylene,” by itself or as part of anotherterm, refers to a saturated, branched or straight chain or cyclichydrocarbon diradical of the stated number of carbon atoms, typically1-6 carbon atoms, and having two monovalent radical centers derived bythe removal of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. Typical alkylene radicals include, but are notlimited to methylene (—CH₂—), 1,2-ethylene (—CH₂CH₂—), 2,2-dimethylene,1,3-propylene (—CH₂CH₂CH₂—), 2-methylpropylene, 1,4-butylene(—CH₂CH₂CH₂CH₂—), and the like; optionally substituted, as appropriate,by 1 to 5 suitable substituents as defined above such as fluoro, chloro,deuteron, cyano, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl. When the compounds ofthe invention contain a C₂₋₆alkenyl group, the compound may exist as thepure E (entgegen) form, the pure Z (zusammen) form, or any mixturethereof.

“Alkylidene” or “alkenyl” refers to a divalent group formed from analkane by removal of two hydrogen atoms from the same carbon atom, thefree valencies of which are part of a double bond, optionallysubstituted as described herein. The term alkylidene also includes“allenes” wherein on carbon atom has double bonds with each of its twoadjacent carbon centers, such as, for example, propadiene. Asappropriate, an alkenyl may be optionally substituted at each carbon asdefined in the claims, optionally substituted, as appropriate, by 1 to 5suitable substituents as defined above and herein such as fluoro,chloro, deutero, cyano, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

“Alkynyl” refers to an aliphatic hydrocarbon having at least onecarbon-carbon triple bond, including straight chain, branched chain orcyclic groups having at least one carbon-carbon triple bond, optionallysubstituted as described herein. Preferably, it is a lower alkynylhaving 2 to 6 carbon atoms. For example, as used herein, the term“C₂₋₆alkynyl” is used herein to mean a straight or branched hydrocarbonchain alkynyl radical as defined above having 2 to 6 carbon atoms andone triple bond. As appropriate, an alkynyl may be optionallysubstituted at each carbon as defined in the claims. Typicalsubstitution includes, but is not limited to, optionally substituted, asappropriate, by 1 to 5 suitable substituents as defined above andherein, such as fluoro, chloro, deutero, cyano, trifluoromethyl,(C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or(C₁-C₆)alkyl.

The term “cycloalkyl” refers to a nonaromatic ring containing 3 to 10carbons that is fully hydrogenated consisting of mono-, bi- or tricyclicrings. Accordingly, a cycloalkyl may be a single ring, which typicallycontains from 3 to 7 ring atoms. Examples include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively,2 or 3 rings may be fused together, such as bicyclodecanyl anddecalinyl. The term “cycloalkyl” also includes bridged bicycloalkylsystems such as, but not limited to, bicyclo[2.2.1]heptane andbicyclo[1.1.1]pentane. The cycloalkyl group may be optionallysubstituted as described herein, as appropriate, by 1 to 5 suitablesubstituents as defined above such as fluoro, chloro, deutero, cyano,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl.

The term “heterocycloalkyl” means a monovalent saturated moiety,consisting of one to three rings, incorporating one, two, three or fourheteroatoms (selected from N, O or S) and three to 10 carbon atoms. Theheterocycloalkyl may be optionally substituted as defined herein.Examples of heterocycloalkyl moieties include, but are not limited to,optionally substituted piperidinyl, piperazinyl, homopiperazinyl,azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl,isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorphilinylsulfone, dihydroquinolinyl, tetrahydroquinolinyl,tetrahydrisoquinolinyl, and the like. Heterocycloalkyls may beoptionally substituted, as appropriate, by 1 to 5 suitable substituentsas defined herein such as fluoro, chloro, deutero, cyano,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl.

Unless otherwise indicated, the term “heteroalkyl,” by itself or incombination with another term, means, unless otherwise stated, asaturated, straight or branched chain hydrocarbon radical consisting ofthe stated number of carbon atoms and from one to three heteroatomsselected from the group consisting of O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) O, N and Smay be placed at any interior position of the heteroalkyl group. Theheteroatom S may be placed at any position of the heteroalkyl group,including the position at which the alkyl group is attached to theremainder of the molecule. Up to two heteroatoms may be consecutive.

Unless otherwise indicated, the term “heteroalkylene” by itself or aspart of another substituent means a divalent group derived fromheteroalkyl (as defined above). For heteroalkylene groups, heteroatomscan also occupy either or both of the chain termini.

The term “alkoxy” and “alkyloxy”, which may be used interchangeably,refers to a moiety of the formula —OR, wherein R is a straight chainsaturated alkyl or branched chain saturated alkyl moiety, as definedherein, bonded through an oxygen atom. The alkoxy group may beoptionally substituted as defined herein. Non-limiting examples of suchalkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tertiary butoxy, pentoxy and the like.

The term “aryl” means a carbocyclic aromatic system containing one ortwo rings wherein such rings may be fused. If the rings are fused, oneof the rings must be fully unsaturated and the fused ring(s) may befully saturated, partially unsaturated or fully unsaturated. The term“fused” means that a second ring is present (i.e., attached or formed)by having two adjacent atoms in common (i.e., shared) with the firstring. The term “fused” is equivalent to the term “condensed”. The arylgroup may be optionally substituted as defined herein. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl, benzo[b][1,4]oxazin-3(4H)-only, 2,3-dihydro-1Hindenyl and 1,2,3,4-tetrahydronaphthalenyl. Aryls may be optionallysubstituted, as appropriate, by 1 to 5 suitable substituents as definedabove such as fluoro, chloro, deutero, cyano, trifluoromethyl,(C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or(C₁-C₆)alkyl.

The term “heteroaryl” refers to an aromatic ring structure containingfrom 5 to 6 ring atoms in which at least one of the ring atoms is aheteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ringatoms being independently selected from the group consisting of carbon,oxygen, nitrogen, and sulfur. Examples of heteroaryl substituentsinclude 6-membered ring substituents such as pyridyl, pyrazyl,pyrimidinyl, and pyridazinyl; and 5-membered ring substituents such astriazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl andisothiazolyl. In a group that has a heteroaryl substituent, the ringatom of the heteroaryl substituent that is bound to the group may be oneof the heteroatoms, or it may be a ring carbon atom. Similarly, if theheteroaryl substituent is in turn substituted with a group orsubstituent, the group or substituent may be bound to one of theheteroatoms, or it may be bound to a ring carbon atom. The term“heteroaryl” also includes pyridyl N-oxides and groups containing apyridine N-oxide ring.

Further examples include furyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyridin-2(1H)-onyl, pyridazin-2(1H)-onyl,pyrimidin-2(1H)-onyl, pyrazin-2(1H)-onyl, imidazo[1,2-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl,5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl,6,7-dihydro-5H-cyclopenta[c]pyridinyl,1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl,6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl. Theheteroaryl can be optionally substituted, as appropriate, by 1 to 5suitable substituents as defined herein such as fluoro, chloro, deutero,cyano, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

Examples of single-ring heteroaryls and heterocycloalkyls includefuranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl,dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl,tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiaoxadiazolyl, oxathiazolyl, oxadiazolyl (includingoxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or1,3,4-oxadiazolyl), pyranyl (including 1,2-pyranyl or 1,4-pyranyl),dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl,pyrimidinyl, piperazinyl, triazinyl (including s-triazinyl, as-triazinyland v-triazinyl), oxazinyl (including 2H-1,2-oxazinyl, 6H-1,3-oxazinyl,or 2H-1,4-oxazinyl), isoxazinyl (including o-isoxazinyl orp-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including2H-1,2,4-oxadiazinyl or 2H-1,2,5-oxadiazinyl), and morpholinyl.

The term “heteroaryl” also includes fused ring systems having one or tworings wherein such rings may be fused, wherein fused is as definedabove. It is to be understood that if a carbocyclic or heterocyclicmoiety may be bonded or otherwise attached to a designated substratethrough differing ring atoms without denoting a specific point ofattachment, then all possible points are intended, whether through acarbon atom or, for example, a trivalent nitrogen atom. For example, theterm “pyridyl” means 2-, 3- or 4-pyridyl, the term “thienyl” means 2- or3-thienyl, and so forth.

In some instances, the number of atoms in a cyclic substituentcontaining one or more heteroatoms (i.e., heteroaryl orheterocycloalkyl) is indicated by the prefix “x- to y-membered”, whereinx is the minimum and y is the maximum number of atoms forming the cyclicmoiety of the substituent. Thus, for example, “5- to 6-memberedheteroaryl” refers to a heteroaryl containing from 5 to 6 atoms,including one or more heteroatoms, in the cyclic moiety of theheteroaryl. The heteroatoms for this invention are selected fromnitrogen, oxygen and sulfur.

Compounds of the present invention may contain basic nitrogen atoms(e.g. alkyl amines or heterocycles such as pyridine etc.) which may beconverted to N-oxides by treatment with an oxidizing agent (e.g. MCPBAand/or hydrogen peroxides) to afford other compounds of this invention.Thus, all nitrogen-containing compounds that may converted to N-oxide (NO or

N+—O−) derivatives are part of the invention.

One skilled in the art would appreciate that metabolites may be formedas part of the natural biochemical process of degrading and eliminatingthe compounds. For example, some compounds of the invention maynaturally form an N-oxide, as depicted below in the compound of FormulaIf′ or in other areas of the compound of Formula Ia. Metabolites such asthese or others formed as part of the natural biochemical process arewithin the scope of the invention.

If substituents are described as “independently” having more than onevariable, each instance of a substituent is selected independent of theother from the list of variables available. Each substituent thereforemay be identical to or different from the other substituent(s).

“Patient” or “subject” refers to warm-blooded animals such as, forexample, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle,goats, sheep, horses, monkeys, chimpanzees, and humans.

The term “pharmaceutically acceptable” means the substance orcomposition must be compatible, chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, delaying theprogression of, delaying the onset of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, unlessotherwise indicated, refers to the act of treating as “treating” isdefined immediately above. The term “treating” also includes adjuvantand neo-adjuvant treatment of a subject. For the avoidance of doubt,reference herein to “treatment” includes reference to curative,palliative and prophylactic treatment, and to the administration of amedicament for use in such treatment.

As used herein, the terms “Formula I”, “Formula Ia”, “Formula IIa-IIg”,“Formula III” and “Formula IIIa” may be hereinafter referred to as a“compound(s) of the invention,” “the present invention,” andcollectively the “compound of Formula I.” Accordingly, the term“compound of Formula I” includes the compounds of Formula Ia, IIa-IIg,III and IIIa. Such terms are also defined to include all forms of thecompound of Formula I, including hydrates, solvates, isomers,crystalline and non-crystalline forms, isomorphs, polymorphs, tautomersand metabolites thereof. For example, the compounds of the invention, orpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms. When the solvent or water is tightly bound, the complexwill have a well-defined stoichiometry independent of humidity. When,however, the solvent or water is weakly bound, as in channel solvatesand hygroscopic compounds, the water/solvent content will be dependenton humidity and drying conditions. In such cases, non-stoichiometry willbe the norm.

The compounds of the invention have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of Formula I maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included.For example, unless stated otherwise, it is intended that the compoundsof Formula I can exist as enantiomers and diastereomers or as racematesand mixtures thereof.

The use of a solid line to depict bonds to one or more asymmetric carbonatoms in a compound of Formula I and the use of a solid or dotted wedgeto depict bonds to other asymmetric carbon atoms in the same compound ismeant to indicate that a mixture of diastereomers is present.

Stereoisomers of Formula I include cis and trans isomers, opticalisomers such as R and S enantiomers, diastereomers, geometric isomers,rotational isomers, conformational isomers, and tautomers of thecompounds of the invention, including compounds exhibiting more than onetype of isomerism; and mixtures thereof (such as racemates anddiastereomeric pairs). Also included are acid addition or base additionsalts wherein the counterion is optically active, for example, D-lactateor L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

The compounds of the invention may exhibit the phenomenon oftautomerism. For example, the compound exemplified by 173 may exist inseveral tautomeric forms, including the pyrrolidin-2-one form, Example173a, and the 5-hydroxy-3,4-dihydro-2H-pyrrol form, Example 173b. Allsuch tautomeric forms are included within the scope of the compounds ofthe Formula I and the scope of the invention. One of ordinary skill inthe art would appreciate and recognize that many of the Examplesdescribed herein may exhibit tautomerism and are within the scope of thecompound of Formula I, Ia, IIa-IIg, III and IIIa. Tautomers exist asmixtures of a tautomeric set in solution. In solid form, usually onetautomer predominates. Even though one tautomer may be described, thepresent invention includes all tautomers of the compounds of theinvention and salts thereof. Examples of tautomers are described byExamples 173a and 173b.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of Formula I with anacid whose anion, or a base whose cation, is generally consideredsuitable for human consumption. Pharmaceutically acceptable salts areparticularly useful as products of the methods of the present inventionbecause of their greater aqueous solubility relative to the parentcompound. For use in medicine, the salts of the compounds of thisinvention are non-toxic “pharmaceutically acceptable salts.” Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention, which are generallyprepared by reacting the free base with a suitable organic or inorganicacid.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids such as acetic,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isothionic, lactic, lactobionic, maleic, malic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids. Suitable organic acids generallyinclude, for example, aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids.

Specific examples of suitable organic acids include acetate,trifluoroacetate, formate, propionate, succinate, glycolate, gluconate,digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate,maleate, fumarate, pyruvate, aspartate, glutamate, benzoate,anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate,mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate,benzenesulfonate, pantothenate, toluenesulfonate,2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate,algenate, β-hydroxybutyrate, galactarate, galacturonate, adipate,alginate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate,picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulfate and hemicalcium salts.

Also within the scope of the present invention are so-called “prodrugs”of the compound of the invention. Thus, certain derivatives of thecompound of the invention that may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into the compound of the invention having the desiredactivity, for example, by hydrolytic cleavage. Such derivatives arereferred to as “prodrugs.” Further information on the use of prodrugsmay be found in “Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriersin Drug Design,” Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association). Prodrugs in accordance with the inventioncan, for example, be produced by replacing appropriate functionalitiespresent in the compounds of any of Formula I with certain moieties knownto those skilled in the art as “pro-moieties” as described, for example,in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).

The present invention also includes isotopically labeled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Compounds of the invention as claimed in the claimsmay specifically define substitution with deutero or deuterium. Theabsence of the term deuteron, deuteron or deuterium, all of which areused interchangeably, in a substitution group shall not be implied toexclude deutero.

Isotopically labeled compounds of Formula I of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

All patents and publications identified herein are incorporated hereinby reference in their entirety and for all purposes.

Compounds of the Invention

In one embodiment, as described above and more fully herein, theinvention is directed to a compound of Formula Ia,

wherein

X and X′ are each independently CR⁸, N or —N⁺—O⁻; Y is independently N,—N⁺—O⁻ or CR^(8′); provided that at least one of X, X or Y is neither Nnor —N⁺—O⁻ and that no more than one of X, X or Y is —N⁺—O⁻; or apharmaceutically acceptable salt of said compound or a tautomer of saidcompound or said salt.

In one aspect, the invention provides for compounds of Formula Iawherein X is N, X′ is CR⁸ and Y is CR′; X is N, X′ is N and Y is CR′; Xis N, X′ is CR⁸ and Y is N; X is CR, X′ and Y are N; X and X′ are CR⁸and Y is N; X is CR⁸ and Y is CR^(8′) and X′ is N; X and X′ are CR⁸ andY is CR′; or a pharmaceutically acceptable salt of said compound or atautomer of said salt. In another aspect, R⁶ is —C(O)NHR⁷, —CO₂R⁷ orcyano; and R⁷ is hydrogen; or a pharmaceutically acceptable salt of saidcompound or a tautomer of said compound or said salt.

The invention also provides for a compound of Formula IIa, IIb, IIc,IId, IIe, IIf or IIg,

wherein R¹ is C₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl;—(CR^(3a)R^(3b))_(m)-(3- to 7-membered cycloalkyl); or—(CR^(3a)R^(3b))_(m)-(3- to 7-membered heterocycloalkyl) having one tothree heteroatoms; wherein said alkyl, alkenyl, alkynyl, cycloalkyl orheterocycloalkyl is optionally substituted with one to five halogen,deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl,C₃-C₆cycloalkyl or —C₁-C₆alkoxy;

R² is —(CR^(3a)R^(3b))_(m)-(3- to 7-membered cycloalkyl), wherein saidcycloalkyl is optionally substituted with one to four R⁴;—(CR^(3a)R^(3b))_(m)-(3- to 7-membered heterocycloalkyl) having one tothree heteroatoms, wherein said heterocycloalkyl is optionallysubstituted at a carbon atom with one to five R⁴ and wherein, if theheteroatom is N, said N is optionally substituted with R^(4′); or R² isC₁-C₆alkyl, wherein said alkyl is optionally substituted with NH₂, cyanoor halogen

R^(3a) and R^(3b) are each independently hydrogen or C₁-C₃alkyl;

R⁴ for each occurrence is independently and optionally halogen, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵, —S(O)R⁹, —S(O)₂R⁹, —C(O)R¹⁰,—(CR^(3a)R^(3b))_(n)-(3- to 7-membered cycloalkyl) or—(CR^(3a)R^(3b))_(n)-(4- to 7-membered heterocycloalkyl) wherein saidalkyl, cycloalkyl or heterocycloalkyl is each optionally andindependently substituted with one to five deuterium, halogen, —OR⁵,—SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkoxyor NR^(11a)R^(11b); or two R⁴ taken together with the respective carbonsto which each are bonded form a 3- to 6-membered cycloalkyl or 4- to6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkylis optionally substituted with one to three halogen, deuterium, —OR⁵,—SR⁵, —NR^(11a)R^(11b), cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein thealkyl or alkoxy is optionally substituted with halogen, deuterium, —OR⁵,—NR^(11a)R^(11b), or cyano; and wherein, if a heteroatom on saidheterocycloalkyl is N, said N is optionally substituted with R^(4′);

R^(4′) is independently C₁-C₆alkyl, C₂-C₆alkenyl, —S(O)R⁹, —S(O)₂R⁹,—C(O)R¹⁰, C(O)(CH₂)_(t)CN; wherein said alkyl is optionally substitutedwith NH₂, cyano or halogen —(CR^(3a)R^(3b))_(n)-(3- to 7-memberedcycloalkyl), or (CR^(3a)R^(3b))_(n)-(4- to 10-memberedheterocycloalkyl), wherein said alkyl, alkenyl, cycloalkyl, orheterocycloalkyl is each optionally and independently substituted withone to five deuterium, halogen, OH, cyano or C₁-C₆alkoxy; or R⁴ andR^(4′) taken together with the respective atoms to which each are bondedform a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl,wherein said cycloalkyl or heterocycloalkyl is optionally substitutedwith one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy isoptionally substituted with halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b) or cyano;

R⁵ is hydrogen or C₁-C₆alkyl, wherein said alkyl is optionallysubstituted with halogen;

R⁶ is —C(O)NHR⁷ or cyano;

R⁷ is hydrogen or C₁-C₆alkyl;

R⁸ is independently hydrogen, halogen, cyano, —NR^(11a)R^(11b),C₁-C₆alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered aryl,wherein said alkyl or heteroaryl or aryl is optionally substituted withone to three halogen, —NR^(11a)R^(11b), C₁-C₃ alkyl or oxo;

R^(8′) is hydrogen, deuterium, halogen, cyano, —OR⁵ or NR^(11a)NR^(11b);

R⁹ is —(CR^(3a)R^(3b))_(p)—(C₁-C₃alkyl), —(CR^(3a)R^(3b))_(p)-(4- to6-membered cycloalkyl), —(CR^(3a)R^(3b))_(p)-(4- to 6-memberedheterocycloalkyl) or —(CR^(3a)R^(3b))_(p)—(C₅-C₉aryl), wherein saidalkyl, cycloalkyl, heterocycloalkyl or aryl is each optionallysubstituted with fluoro or C₁-C₃alkyl;

R¹⁰ is C₁-C₆alkyl, wherein said alkyl is optionally substituted withfluoro or cyano;

R^(11a) and R^(11b) are each independently hydrogen or C₁-C₆alkyl,wherein said alkyl is optionally substituted with OH;

m is independently 0, 1 or 2;

n is independently 0 or 1;

p is independently 0 or 1; and

t is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt of said compound or a tautomer ofsaid compound or said salt.

In one aspect of the invention, R¹ is C₁-C₄alkyl; C₂-C₄alkenyl;C₂-C₄alkynyl; —(CR^(3a)R^(3b))_(m)-(3- to 6-membered cycloalkyl); or—(CR^(3a)R^(3b))_(m)-(3- to 5-membered heterocycloalkyl) having one tothree heteroatoms; wherein said alkyl, alkenyl, alkynyl, cycloalkyl orheterocycloalkyl is optionally substituted with one to three halogen,deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl,C₃-C₆cycloalkyl or C₁-C₆alkoxy; R^(3a) and R^(3b) are each independentlyhydrogen or C₁-C₃alkyl; R⁶ is —C(O)NHR⁷ or cyano; R⁷ is hydrogen; and mis independently 0 or 1.

In another aspect, the invention provides for compounds wherein R¹ isfluoromethyl; difluoromethyl; trifluoromethyl; methyl, ethyl, propyl orisopropyl, each optionally substituted with one to three fluoro ordeuterium; allene, propargyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclopropylmethyl, oxetane or tetrahydrofuran, each of which isoptionally substituted with fluoro or C₁-C₃ alkyl.

In another aspect, R² is selected from pyrrolidinyl, pyrrolidin-2-onyl,piperidinyl, piperidin-2-onyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl,oxazolidinyl, oxazolidin-2-onyl, 1,3-oxazinan-2-onyl, imidazolidinyl,imidazolidin-2-onyl, morpholinyl, morpholin-3-onyl, thiazyl, isothiazyl,isothiazolidine-1,1-dioxidyl, 1,2-thiazinane 1,1-dioxidyl,hexahydrocyclopenta[b]pyrrol-2(1H)-onyl, octahydrocyclopenta[c]pyrrolyl,azetidinyl, hexahydro-1H-indol-2(3H)-onyl, octahydro-1H-isoindolyl,azepanyl, tetrahydrofuranyl, 1,3-dioxolanyl, oxetanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4-azepanyl, 1,4-oxazepanyl,tetrahydro-2H-pyranyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl,cyclohex-2-enyl, or 1,2,3,4-tetrahydroisoquinolinyl; wherein said alkyl,cycloalkyl or heterocycloalkyl is optionally substituted with one tofour R⁴.

In another aspect, the cycloalkyl and heterocycloalkyl of R² isoptionally substituted with one to four R⁴; or two R⁴ taken togetherwith the respective carbons to which each are bonded form a 3- to6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein saidcycloalkyl or heterocycloalkyl is optionally substituted with one tothree F, Cl, OH, cyano, C₁-C₃alkyl (optionally substituted with OH, F orCl), C₁-C₃fluoroalkyl or C₁-C₆alkoxy; R^(q) is independently hydrogen,deuterium or C₁-C₃alkyl, wherein said alkyl is optionally substitutedwith halogen; R^(3a) and R^(3b) for each occurrence are independentlyhydrogen or C₁-C₃alkyl; R⁴ for each occurrence is independently andoptionally halogen; C₁-C₃alkyl; C₂-C₄alkenyl; oxo; —OR⁵; —C(O)R¹⁰;—(CR^(3a)R^(3b))_(n)-(3- to 5-membered cycloalkyl); or—(CR^(3a)R^(3b))_(n)-(4- to 7-membered heterocycloalkyl) wherein saidalkyl, cycloalkyl or heterocycloalkyl is each optionally andindependently substituted with one to five deuterium, halogen, OH,cyano, C₁-C₆alkoxy or —NR^(11a)R^(11b); or two R⁴ taken together withthe respective carbons to which each are bonded form a cyclopropyl,cyclobutyl or cyclopentyl, wherein said cyclopropyl, cyclobutyl orcyclopentyl are optionally substituted with one to three halogen, OH,methyl, ethyl, propyl, C₁-C₃fluoroalkyl, C₁-C₃hydroxyalkyl, methoxy orethoxy; or two R⁴ taken together with the respective carbons to whicheach are bonded form a 4- to 6-membered heterocycloalkyl, wherein saidheterocycloalkyl is optionally substituted with one to three fluoro,C₁-C₃alkyl, or C₁-C₃fluoroalkyl; R⁵ is hydrogen, methyl or ethyl; R⁹ isphenyl; R¹⁰ is C₁-C₆alkyl, wherein said alkyl is optionally substitutedwith fluoro or cyano; and R^(11a) and R^(11b) are each independently Hor C₁-C₆alkyl; or a pharmaceutically acceptable salt thereof or atautomer of said compound or said salt.

In another aspect, R⁴ is selected from F, Cl, OH; C₁-C₃alkyl, optionallysubstituted with one to five deuterium, Cl, F, OH, C₁-C₃alkyl,C₁-C₃alkoxy; or two R⁴ taken together with the respective carbons towhich each are bonded form a cyclopropyl, cyclobutyl or cyclopentyl,wherein said cyclopropyl, cyclobutyl or cyclopentyl are optionallysubstituted with one to three Cl, F, OH, methyl, ethyl, propyl,C₁-C₃fluoroalkyl, C₁-C₃hydroxyalkyl, methoxy or ethoxy; or two R⁴ takentogether with the respective carbons to which each are bonded form a 4-to 6-membered heterocycloalkyl, wherein said heterocycloalkyl isoptionally substituted with one to three fluoro, C₁-C₃alkyl,C₁-C₃fluoroalkyl, —C(O)(CH₂)_(t)CN; or a pharmaceutically acceptablesalt thereof or a tautomer of said compound or said salt.

In another embodiment, the invention is directed to a compound ofFormula III

wherein

X and X′ are each independently CR⁸ or N; Y is independently N orCR^(8′); provided that at least one of X, X′ or Y is not N;

R¹ is C₁-C₆alkyl or C₁-C₆cycloalkyl, wherein said alkyl or cycloalkyl isoptionally substituted with deuterium, halogen, OH, cyano, C₁-C₃alkyl,C₃-C₆cycloalkyl, C₁-C₆alkoxy or C₁-C₆alkylthiolyl;

R^(3a) and R^(3b) are each independently hydrogen or C₁-C₃alkyl;

R⁴ for each occurrence (one, two, three, four or five) is independentlyand optionally halogen, C₁-C₆alkyl, C₂-C₆alkenyl —OR⁵,—(CR^(3a)R^(3b))_(n)-(3- to 6-membered cycloalkyl) or—(CR^(3a)R^(3b))_(n)-(4- to 6-membered heterocycloalkyl) wherein saidalkyl, cycloalkyl or heterocycloalkyl is each optionally andindependently substituted with one to five deuterium, halogen, OH, CN,—C(O)(CH₂)_(t)CN or —C₁-C₆alkoxy; —NR^(11a)R^(11b); two R⁴ takentogether with the respective carbons to which each are bonded form acyclopropyl, cyclobutyl or cyclopentyl, wherein said cyclopropyl,cyclobutyl or cyclopentyl is optionally substituted with one to three F,Cl, OH, methyl, ethyl, propyl, C₁-C₃fluoroalkyl, C₁-C₃difluoroalkyl,C₁-C₃trifluoroalkyl, C₁-C₃hydroxyalkyl, methoxy or ethoxy;

R⁵ is hydrogen or C₁-C₆alkyl, wherein said alkyl is optionallysubstituted with fluoro;

R⁸ is independently hydrogen, halogen, cyano, —NR^(11a)R^(11b),C₁-C₆alkyl, 5- to 6-membered heteroaryl or aryl, wherein said alkyl orheteroaryl or aryl is optionally substituted with one, two or threehalogen, —NR^(11a)R^(11b), C₁-C₃ alkyl or oxo;

R^(8′) is hydrogen, deuterium, halogen or cyano;

R¹⁰ is C₁-C₆alkyl, wherein said alkyl is optionally substituted withfluoro or cyano;

R^(11a) and R^(11b) are each independently hydrogen or C₁-C₆alkyl,wherein said alkyl is optionally substituted with OH;

n is independently 0 or 1; and

t is 1, 2 or 3;

or a pharmaceutically acceptable salt of said compound or a tautomer ofsaid compound or said salt.

In one aspect, the invention is directed to compounds wherein n Y is N;X and X′ are CR⁸. In another aspect, X and X′ are each CR⁸ and Y isCR^(8′) In another aspect, X and Y are N and X′ is CR⁸. In anotheraspect, X is N, X is CR and Y is CR^(8′).

In another aspect, R¹ is C₁-C₃alkyl, wherein said alkyl is optionallysubstituted with one to three deuterium, F, Cl or C₁-C₃alkoxy; andR^(3a) and R^(3b) are each independently hydrogen or methyl. In anotheraspect, R⁴ for each occurrence is independently and optionally F; Cl;OH; or C₁-C₃alkyl, optionally substituted with one to five deuterium,Cl, F, OH, C₁-C₃alkyl, or C₁-C₃alkoxy; or two R⁴ taken together with thecarbons to which they are bonded forma cyclopropyl, cyclobutyl orcyclopentyl, wherein said cyclopropyl, cyclobutyl or cyclopentyl isoptionally substituted with one to three Cl, F, OH, methyl, ethyl,C₁-C₃haloalkyl, C₁-C₃dihaloalkyl, C₁-C₃trihaloalkyl, C₁-C₃hydroxyalkyl,methoxy or ethoxy; or two R⁴ taken together with the carbons to whichthey are bonded form a 4- to 6-membered heterocycloalkyl, wherein saidheterocycloalkyl is optionally substituted with one to three fluoro,C₁-C₃alkyl, C₁-C₃fluoroalkyl or —C(O)(CH₂)_(t)CN.

In still another aspect, R¹ is methyl, ethyl, propyl or isopropylwherein each of said R¹ moieties are optionally substituted withdeuterium, fluoro or methoxy; R⁴ is independently and optionallyselected from fluoro, OH, methyl, ethyl, vinyl, propyl, wherein saidmethyl, ethyl, vinyl or propyl are optionally substituted with one, twoor three fluoro, OH or methoxy; or two R⁴ taken together with thecarbons to which they are bonded form a cyclopropyl, cyclobutyl orcyclopentyl, wherein said cyclopropyl, cyclobutyl or cyclopentyl areoptionally substituted with one to three Cl, F, OH, methyl,fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxymethyl,propyl, C₁-C₃haloalkyl, C₁-C₃dihaloalkyl, C₁-C₃trihaloalkyl,C₁-C₃hydroxyalkyl, methoxy, or ethoxy; and R⁸ is independently hydrogen,halogen or C₁-C₆alkyl, wherein said alkyl is optionally substituted withfluoro.

In another embodiment, the invention is directed to a compound ofFormula IIIa,

wherein

X and X′ are each independently CR⁸ or N; Y is independently N orCR^(8′); provided that at least one of X, X or Y is not N;

R¹ is C₁-C₆alkyl, wherein said alkyl is optionally substituted withdeuterium, halogen, OH, C₁-C₃alkyl, C₃-C₆cycloalkyl or C₁-C₆alkoxy;

R^(3a) and R^(3b) are each independently hydrogen or C₁-C₃alkyl;

R^(4a) and R^(4b) are each independently hydrogen, deuterium, fluoro,OH, —OR⁵, methyl, ethyl, vinyl, cyclopropyl or propyl, optionallysubstituted with one to five deuterium, fluoro, methoxy or OH;

R^(4c) and R^(4d) for each occurrence are independently and optionallyhalogen, OH, deuterium, C₁-C₆alkyl, C₂-C₆alkenyl, —OR⁵,—(CR^(3a)R^(3b))_(n)-(3- to 6-membered cycloalkyl), or—(CR^(3a)R^(3b))_(n)-(4- to 6-membered heterocycloalkyl) wherein saidalkyl, cycloalkyl and heterocycloalkyl are each optionally andindependently substituted with one to five deuterium, halogen, OH,cyano, or C₁-C₆alkoxy; NH₂; or R^(4c) and R^(4d) taken together with thecarbons to which they are bonded form a 4- to 7-memberedheterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein saidheterocycloalkyl or cycloalkyl is optionally substituted with one tothree fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl; or

R^(4a) and R^(4c) taken together with the carbon to which they arebonded form a 4- to 7-membered heterocycloalkyl or a 3- to 7-memberedcycloalkyl, wherein said heterocycloalkyl or cycloalkyl is optionallysubstituted with one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;

R⁵ is hydrogen or C₁-C₆alkyl, wherein said alkyl is optionallysubstituted with fluoro;

R⁸ is hydrogen, halogen or C₁-C₆alkyl, wherein said alkyl is optionallysubstituted with halogen;

R^(8′) is hydrogen, deuterium, halogen or cyano; and

n is independently 0 or 1;

or a pharmaceutically acceptable salt of said compound or a tautomer ofsaid compound or said salt.

In one aspect, the invention provides R⁶ is hydrogen, methyl or fluoro;R¹ is methyl, ethyl, isopropyl or propyl, optionally substituted withdeuterium; R^(4a) is hydrogen; methyl, ethyl or propyl, optionallysubstituted with deuterium, fluoro, methoxy; R^(4b) is hydrogen orfluoro; R^(4c) is hydrogen or OH; R^(4d) is hydrogen, fluoro, methoxy orOH; or methyl, optionally substituted with 1, 2 or 3 fluoro; or ethyl,optionally substituted with 1, 2, or 3 fluoro; or R^(4c) and R^(4d) oralternatively R^(4a) and R^(4c) taken together with the carbons to whichthey are bonded form a cyclopropyl, optionally substituted with one tothree fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl; or a pharmaceuticallyacceptable salt of said compound or a tautomer of said compound or saidsalt.

In another embodiment, the invention is directed to the compoundsdescribed in Tables 1 or 3; or a pharmaceutically acceptable salt ofsaid compound or a tautomer of said compound or said salt.

In another embodiment, the invention is directed to the intermediatecompounds described in Table 2; or a pharmaceutically acceptable salt ofsaid compound or a tautomer of said compound or said salt

In another embodiment, the invention is directed to a synthetic processand preparation of the intermediate compounds described in Table 2, asdetailed in the Schemes and the preparation section described herein. Inanother aspect, the invention is directed to a synthetic process andpreparation of the compounds of Tables 1 or 3, as detailed in theSchemes and the preparation section described herein.

IRAK4 Indications

The compounds of the invention are also useful in treating and/orpreventing a disease or condition mediated by or otherwise associatedwith an IRAK enzyme; the method comprising administering to a subject inneed thereof an effective amount of a compound of the invention.

The disease may be, but not limited to, one of the following classes:auto-immune diseases, inflammatory diseases, allergic diseases,metabolic diseases, infection-based diseases, trauma or tissue-injurybased diseases, fibrotic diseases, genetic diseases, diseases driven byover-activity of IL1 pathways, cardiovascular diseases, vasculardiseases, heart diseases, neurological diseases, neurodegenerativediseases, respiratory diseases, pulmonary diseases, airways diseases,renal diseases, skin and/or dermatological diseases, liver diseases,gastrointestinal diseases, oral diseases, pain and sensory diseases,hematopoietic diseases, joint diseases, muscle diseases, bone diseases,and ophthalmic and/or ocular diseases.

Specific autoimmune diseases include, but are not limited to: rheumatoidarthritis, osteoarthritis, psoriasis, allergic dermatitis, systemiclupus erythematosus (and resulting complications), Sjögren's syndrome,multiple sclerosis, asthma, glomerular nephritis, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease, ankylosingspondylitis, Behçet's disease, lupus nephritis, scleroderma, systemicscleroderma, type 1 or juvenile on-set diabetes, alopecia universalis,acute disseminated encephalomyelitis, Addison's disease,antiphospholipid antibody syndrome, atrophic gastritis of perniciousanemia, autoimmune alopecia, autoimmune hemolytic anemia, autoimmunehepatitis, autoimmune encephalomyelitis, autoimmune thrombocytopenia,Bullous pemphigoid, Chagas disease, Celiac disease, chronic hepatitis,Cogan's syndrome, dermatomyositis, endometriosis, Goodpasture'ssyndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease(or Hashimoto's thyroiditis), hemolytic anemia, hidradentitissuppurativa, idiopathic thrombocytopenia purpura, interstitial cystitis,membranous glomerulopathy, morphea, mystenia gravis, narcolepsy,pemphigus, pernicous anemia, polyarteritis nodosa, polymyositis, primarybiliary cirrhosis, Reiter's syndrome, schizophrenia, symphatheticopthalmia, systemic sclerosis, temporal arteritis, thyroiditis,vasculitis, vitiglio, vulvodynia, Wegner's granulomatosis, palmoplantarkeratoderma, systemic-onset Juvenile Idiopathic Arthritis (SJIA), or anindication listed in a separate category herein.

Specific inflammatory diseases include, but are not limited to: chronicobstructive pulmonary diseases, airway hyper-responsiveness, cysticfibrosis, acute respiratory distress syndrome, sinusitis, rhinitis,gingivitis, atherosclerosis, chronic prostatitis, glomerular nephritis,ulcerative colitis, uveitis, periodontal disease, or an indicationlisted in a separate category herein.

Specific pain conditions include, but are not limited to: inflammatorypain, surgical pain, visceral pain, dental pain, premenstrual pain,central pain, pain due to burns, migraine or cluster headaches, nerveinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injury, pain associated withirritable bowel syndrome, gout, pain associated with any of the otherindications listed within this specification, or an indication listed ina separate category herein.

Specific respiratory, airway and pulmonary conditions include, but arenot limited to: asthma (which may encompass chronic, late, bronchial,allergic, intrinsic, extrinsic or dust), chronic obstructive pulmonarydisease, idiopathic pulmonary fibrosis, pulmonary arterial hypertension,cystic fibrosis, interstitial lung disease, acute lung injury,sarcoidosis, allergic rhinitis, chronic cough, bronchitis, recurrentairway obstruction, emphysema, or bronchospasm, or an indication listedin a separate disease category herein.

Specific gastrointestinal (GI) disorders include, but are not limitedto: Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD),biliary colic and other biliary disorders, renal colic,diarrhea-dominant IBS, pain associated with GI distension, ulcerativecolitis, Crohn's Disease, irritable bowel syndrome, Celiac disease,proctitis, eosinophilic gastroenteritis, mastocytosis, or an indicationlisted in a separate disease category herein.

Specific allergic diseases include, but are not limited to: anaphylaxis,allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema,allergic asthma, allergic reactions to: food, drugs, insect bites,pollen; or an indication listed in a separate disease category herein.

Specific infection-based diseases include, but are not limited to:sepsis, septic shock, viral diseases, malaria, Lyme disease, ocularinfections, conjunctivitis, Whipple Disease, or an indication listed ina separate disease category herein.

Specific trauma and tissue injury-based conditions include, but are notlimited to: Renal glomerular damage, reperfusion injury (for example toheart, kidney, lung), spinal cord injury, tissue scarring, tissueadhesion, tissue repair, transplant rejection (for examples to heart,lung, bone marrow, cartilage, cornea, kidney, limb, liver, muscle,myoblast, pancreas, pancreatic islet, skin, nerve, small intestine,trachea), hypersensitivities, or an indication listed in a separatedisease category herein.

Specific fibrotic diseases include, but are not limited to: Idiopathicpulmonary fibrosis, liver fibrosis, renal fibrosis, or an indicationlisted in a separate disease category herein.

Specific diseases considered to be driven by over-activity of IL1pathways include, but are not limited to: Cryopyrin-associated periodicsyndromes, myositis, and indications included in the following reviewarticle: C. A. Dinarello, A. Simon and J. W. M. van der Meer, Treatinginflammation by blocking interleukin-1 in a broad spectrum of diseases,Nat Rev Drug Discov, 2012, 11(8), 633-652,http/dx.doi.org/10.1038/nrd3800 and supplementary information containedtherein, or an indication listed in a separate disease category herein.

Specific ophthalmic/ocular diseases include, but are not limited to:uveitis, age-related macular degeneration, diabetic macular edema,keratoconjuctivitis, uveitis associated with Behçet's disease, vernalconjunctivitis, ketatitis, lens-induced uveitis, herpetic keratitis,conical keratitis, corneal epithelial dystrophy, ocular pemphigus,Mooren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Haradasyndrome, keratoconjunctivitis sicca, phlyctenule, iridocyclitis,sympathetic ophthalmia, allergic conjunctivitis, ocularneovascularization, dry eye syndrome, or an indication listed in aseparate disease category herein.

Specific joint, muscle and bone disorders include, but are not limitedto: osteoarthritis, osteoporosis, rheumatoid arthritis, juvenilearthritis, psoriatic arthritis, erosive osteoarthritis of the hand,arthrofibrosis/traumatic knee injury, anterior cruciate knee ligamenttear, relapsing polychondritis, recurrent multifocal osteomyelitis,Majeed Syndrome, ankylosing spondylitis, gout of the lumbar spine,antisynthetase syndrome, idiopathic inflammatory myopathies, articularchondrocalcinosis, systemic-onset Juvenile Idiopathic Arthritis (SJIA),gout and pyrophosphate crystal arthritis, or an indication listed in aseparate disease category herein.

Specific skin/dermatological diseases include, but are not limited to:psoriasis, atopic dermatitis, cutaneous lupus, acne, dermatomyositis,eczema, pruritus, scleroderma, Sweet Syndrome/neutrophilic dermatosis,neutrophilic panniculitis, acrodermatitis (form of pustular psoriasis),or an indication listed in a separate disease category herein.

Specific renal diseases include, but are not limited to: acute kidneyinjury (AKI) (sepsis-AKI, coronary artery bypass graft-AKI, cardiacsurgery-AKI, non-cardiac surgery-AKI, transplant surgery-AKIcisplatin-AKI, contrast/imaging agent induced-AKI), glomerulonephritis,IgA nephropathy, crescentic GN, lupus nephritis, HIV associatednephropathy, membraneous nephropathy, C3 glomerulopathy, Dense depositdisease, ANCA vasculitis, diabetic nephropathy, hemolytic-uremicsyndrome, atypical Hemolytic-uremic syndrome, nephrotic syndrome,nephritic syndrome, hypertensive nephrosclerosis, ApoL1 nephropathy,focal segmental glomerulosclerosis, Alport syndrome, Fanconi, syndrome,crystal nephropathy, nephrolithiasis, nephrotic syndrome, renaltransplant rejection, amyloidosis, glomerulonephritis in SJIA, or anindication listed in a separate disease category herein.

Specific genetic diseases include, but are not limited to: FamilialMediterranean fever (FMF), CAPS (FCAS, Muckle-Wells Syndrome,NOMID/CINCA), male hypoinfertility in CAPS, NLRP12 AutoinflammatorySyndrome, or an indication listed in a separate disease category herein.

Specific hematopoietic diseases include, but are not limited to:hemolytic anemia, or an indication listed in a separate disease categoryherein.

Specific liver diseases include, but are not limited to: liver fibrosis,liver cirrhosis, nonalcoholic steatohepatitis (NASH), or an indicationlisted in a separate disease category herein.

Specific oral diseases include, but are not limited to: gingivitis,periodontal disease or an indication listed in a separate diseasecategory herein.

Specific metabolic diseases include, but are not limited to: Type 2diabetes (and resulting complications), gout and hyperuricemia,metabolic syndrome, insulin resistance, obesity, or an indication listedin a separate disease category herein.

Compounds of the current invention are also useful in the treatment of aproliferative disease selected from a benign or malignant tumor, solidtumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder,breast, stomach, gastric tumors, ovaries, colon, rectum, prostate,pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,nonsmall-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, smoldering of indolent multiplemyeloma, or hematological malignancies (including leukemia, diffuselarge B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia(CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma), or an indication listed in aseparate disease category herein.

Cardiovascular conditions include, but are not limited to coronary heartdisease, acute coronary syndrome, ischaemic heart disease, first orrecurrent myocardial infarction, secondary myocardial infarction, non-STsegment elevation myocardial infarction, or ST segment elevationmyocardial infarction, ischemic sudden death, transient ischemic attack,peripheral occlusive arterial disease, angina, atherosclerosis,hypertension, heart failure (such as congestive heart failure),diastolic dysfunction (such as left ventricular diastolic dysfunction,diastolic heart failure, and impaired diastolic filling), systolicdysfunction (such as systolic heart failure with reduced ejectionfraction), vasculitis, ANCA vasculitis, post-myocardial infarctioncardiac remodeling atrial fibrillation, arrhythmia (ventricular),ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardialand vascular fibrosis, impaired arterial compliance, myocardial necroticlesions, vascular damage, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, fibrinoid necrosis of coronary arteries, adverseremodeling, stroke, and the like, or an indication listed in a separatedisease category herein. Also, included are venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis. It is noted that thrombosis includes occlusion(e.g., after a bypass) and reocclusion (e.g., during or afterpercutaneous transluminal coronary angioplasty).

Cardiovascular complications of type 2 diabetes are associated withinflammation, accordingly, the compounds of the present invention may beused to treat diabetes and diabetic complications such as macrovasculardisease, hyperglycemia, metabolic syndrome, impaired glucose tolerance,hyperuricemia, glucosuria, cataracts, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension,hyperinsulinemia, and insulin resistance syndrome, or an indicationlisted in a separate disease category herein.

Linkage of innate immunity and inflammation to disease has beendemonstrated in neuroinflammatory and neurodegenerative conditions.Therefore, the compounds of the present invention are particularlyindicated for use in the treatment of neuroinflammatory andneurodegenerative conditions (i.e., disorders or diseases) in mammalsincluding humans such as multiple sclerosis, migraine; epilepsy;Alzheimer's disease; Parkinson's disease; brain injury; stroke;cerebrovascular diseases (including cerebral arteriosclerosis, cerebralamyloid angiopathy, hereditary cerebral hemorrhage, and brainhypoxia-ischemia); cognitive disorders (including amnesia, seniledementia, HIV associated dementia, Alzheimer's associated dementia,Huntington's associated dementia, Lewy body dementia, vascular dementia,drug related dementia, delirium, and mild cognitive impairment); mentaldeficiency (including Down syndrome and fragile X syndrome); sleepdisorders (including hypersomnia, circadian rhythm sleep disorder,insomnia, parasomnia, and sleep deprivation) and psychiatric disorders(such as anxiety (including acute stress disorder, generalized anxietydisorder, social anxiety disorder, panic disorder, post-traumatic stressdisorder and obsessive-compulsive disorder); factitious disorder(including acute hallucinatory mania); impulse control disorders(including compulsive gambling and intermittent explosive disorder);mood disorders (including bipolar I disorder, bipolar II disorder,mania, mixed affective state, major depression, chronic depression,seasonal depression, psychotic depression, and postpartum depression);psychomotor disorder; psychotic disorders (including schizophrenia,schizoaffective disorder, schizophreniform, and delusional disorder);drug dependence (including narcotic dependence, alcoholism, amphetaminedependence, cocaine addiction, nicotine dependence, and drug withdrawalsyndrome); eating disorders (including anorexia, bulimia, binge eatingdisorder, hyperphagia, and pagophagia); and pediatric psychiatricdisorders (including attention deficit disorder, attentiondeficit/hyperactive disorder, conduct disorder, and autism), myotrophiclateral sclerosis, chronic fatigue syndrome, or an indication listed ina separate disease category herein.

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention are administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds required to treat the progress of the medical conditionare readily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts.

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed, by which the compound enters the blood stream directly fromthe mouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beadministered topically to the skin or mucosa, that is, dermally ortransdermally. In another embodiment, the compounds of the invention canalso be administered intranasally or by inhalation. In anotherembodiment, the compounds of the invention may be administered rectallyor vaginally. In another embodiment, the compounds of the invention mayalso be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing from about 0.01 mg to about 500 mg of the activeingredient, or in another embodiment, from about 1 mg to about 100 mg ofactive ingredient. Intravenously, doses may range from about 0.1 toabout 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compound ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of Formula I areordinarily combined with one or more adjuvants. Such capsules or tabletsmay contain a controlled-release formulation. In the case of capsules,tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.

Injectable preparations (e.g., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting agents, and/or suspending agents.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound that enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibers, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated; see, for example, J. Pharm. Sci., 88(10),955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g., absorbable gel sponges,collagen) and non-biodegradable (e.g., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as cross-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially.

Two or more compounds may be administered simultaneously, concurrentlyor sequentially. Additionally, simultaneous administration may becarried out by mixing the compounds prior to administration or byadministering the compounds at the same point in time but at differentanatomic sites or using different routes of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention includes the use of a combination of an IRAKinhibitor compound as provided in the compound of Formula I and one ormore additional pharmaceutically active agent(s). If a combination ofactive agents is administered, then they may be administeredsequentially or simultaneously, in separate dosage forms or combined ina single dosage form. Accordingly, the present invention also includespharmaceutical compositions comprising an amount of: (a) a first agentcomprising a compound of Formula I or a pharmaceutically acceptable saltof the compound; (b) a second pharmaceutically active agent; and (c) apharmaceutically acceptable carrier, vehicle or diluent.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thata compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect. Thus, the methods of prevention and treatment described hereininclude use of combination agents.

The combination agents are administered to a mammal, including a human,in a therapeutically effective amount. By “therapeutically effectiveamount” it is meant an amount of a compound of the present inventionthat, when administered alone or in combination with an additionaltherapeutic agent to a mammal, is effective to treat the desireddisease/condition e.g., inflammatory condition such as systemic lupuserythematosus. See also, T. Koutsokeras and T. Healy, Systemic lupuserythematosus and lupus nephritis, Nat Rev Drug Discov, 2014, 13(3),173-174, for therapeutic agents useful treating lupus.

In particular, it is contemplated that the compounds of the inventionmay be administered with the following therapeutic agents:

Non-steroidal anti-inflammatory drugs (NSAIDs), including but notlimited to, non-selective COX1/2 inhibitors such as piroxicam, naproxen,flubiprofen, fenoprofen, ketoprofen, ibuprofen, etodolac (Lodine),mefanamic acid, sulindac, apazone, pyrazolones (such as phenylbutazone),salicylates (such as aspirin); selective COX2 inhibitors such as:celecoxib, rofecoxib, etoricoxib, valdecoxib, meloxicam;

Immunomodulatory and/or anti-inflammatory agents, including but notlimited to, methotrexate, leflunomide, ciclesonide chloroquine,hydroxychloroquine, d-penicillamine, auranofin, sulfasalazine, sodiumaurothiomalate, cyclosporine, azathioprine, cromolyn, hydroxycarbamide,retinoids, fumarates (such as monomethyl and dimethyl fumarate),glatiramer acetate, mitoxantrone, teriflunomide, suplatast tosilate,mycophenolate mofetil and cyclophosphamide, laquinimod, voclosporin,PUR-118, AMG 357, AMG 811, BCT197;

Antimalarials, including but not limited to, hydroxychloroquine(Plaquenil) and chloroquine (Aralen), cyclophosphamide (Cytoxan),methotrexate (Rheumatrex), azathioprine (Imuran), mesalamine (Asacol)and sulfasalazine (Azulfidine):

Antibiotics, including but not limited to, Flagyl or ciprofloxacin;

Anti-TNFα agents, including but not limited to, infliximab, adalimumab,certolizumab pegol, golimumab and etanercept;

Anti-CD20 agents, including but not limited to, rituximab, ocrelizumab,ofatumumab and PF-05280586;

Antidiarrheals, such as diphenoxylate (Lomotil) and loperamide(Imodium);

Bile acid binding agents, such as cholestyramine, alosetron (Lotronex)and ubiprostone (Amitiza);

Laxatives, such as Milk of Magnesia, polyethylene glycol (MiraLax),Dulcolax, Correctol and Senokot, and anticholinergics or antispasmodicssuch as dicyclomine (Bentyl);

T lymphocyte activation inhibitors, including but not limited to,abatacept:

Anti-IL1 treatments, including but not limited to, anakinra, rilonacept,canakinumab, gevokizumab, MABp1 and MEDI-8968;

Glucocorticoid receptor modulators that may be dosed orally, byinhalation, by injection, topically, rectally, by ocular delivery,including but not limited to, betamethasone, prednisone, hydrocortisone,prednisolone, flunisolide, triamcinoline acetonide, beclomethasone,dipropionate, budesonide, fluticasone propionate, ciclesonide,mometasone furoate, fluocinonide, desoximetasone, methylprednisolone orPF-04171327;

Aminosalicyic acid derivatives, including but not limited to,sulfasalazine and mesalazine; Anti-α4 integrin agents, including but notlimited to, natalizumab;

α1- or α2-adrenergic agonist agents including but not limited to:propylhexidrine, phenylephrine, phenylpropanolamine, pseudoephedrine ornaphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride or ethylnorepinephrinehydrochloride;

β-adrenergic agonists, including but not limited to, metaproterenol,isoprotenerol, isoprenaline, albuterol, salbutamol, formoterol,salmeterol, terbutaline, orciprenaline, botolterol mesylate, pirbuterol;

Anticholinergic agents, including but not limited to, ipratropiumbromide, tiotropium bromide, oxitropium bromide, aclindinium bromide,glycopyrrolate, pirenzipine or telenzepine;

Inhaled long acting beta-agonists, long acting muscarinic antagonistsand long acting corticosteroids, including but not limited, to thoseincluded in the following reference: Y. Mushtaq, The COPD pipeline, NatRev Drug Discov, 2014, 13(4), 253-254. http://dx.doi_org/10.1038/nrd425;

Leukotriene pathway modulators, including but not limited to, 5-LOInhibitors (such as zileuton), FLAP antagonists (such as veliflapon,fiboflapon), LTD4 antagonists (such as montelukast, zafirlukast orpranlukast;

H1 receptor antagonists, including but not limited to, cetirizine,loratidine, desloratidine, fexofenadine, astemizole, azelastine orchlorpheniramine;

PDE4 inhibitors, including but not limited to, apremilast, roflumilastor AN2728;

Vitamin D receptor modulators, including but not limited to,paricalcitol;

Nrf2 pathway activators, including but not limited to, fumarates,sulfurophane and bardoxolone methyl;

Modulators of the RAR-related orphan receptor (ROR) family, inparticular RORg;

Modulator and/or antagonists of the chemokine receptors, including butnot limited to, CCR2 antagonists (such as CCX140, BMS-741672,PF-4634817, CCX-872, NOX-E36), CCR2/5 antagonists (such as PF-4634817),CCR9 (such as vercirnon, CCX507), CCR1 modulators, CCR4 modulators, CCR5modulators, CCR6 modulators, CXCR6 modulators, CXCR7 modulators) andCXCR2 modulators (such as danirixin, AZD5069);

Prostaglandins, including but not limited to, prostacyclin;

PDE5 inhibitors, including but not limited to, sildenafil, PF-489791,vardenafil and tadalafil;

Endothelin receptor antagonists, including but not limited to, bosentan,ambrisentan, sparsentan, atrasentan, zibotentan and macitentan;

Soluble guanylate cyclase activators, including but not limited to,riociguat;

Interferons, including but not limited to, interferon beta-1a interferonbeta-1b;

Sphingosine 1-phosphate receptor modulators, including but not limitedto, fingolimod, ponesimod;

Inhibitors of the complement pathway, including but not limited to, C5aRantagonists (such as CCX168, PMX-53, NN8210), C5 inhibitors (such aseculizumab), inhibitors of complement factors B and D, inhibitors ofMASP2 (such as OMS-721) and ARC-1905;

Inhibitors of Janus kinases (one of more of JAK1, JAK2, JAK3, TYK2),including but not limited to, decernotinib, cerdulatinib, JTE-052,ruxolitinib, tofacitnib, Baricitinib, Peficitinib, GLPG-0634,INCB-47986, INCB-039110, PF-04965842, XL-019, ABT-494, R-348,GSK-2586184, AC-410, BMS-911543 and PF-06263276;

Inhibitors of other anti-inflammatory or immunomodulatory kinases,including but not limited to, spleen tyrosine kinase (SYK) inhibitors,p38 MAP kinase inhibitors (such as PF-3715455, PH-797804, AZD-7624,AKP-001, UR-13870, FX-005, semapimod, pexmetinib, ARRY-797, RV-568,dilmapimod, ralimetinib), PI3K inhibitors (such as GSK-2126458,pilaralisib, GSK-2269557), PI3Kg and/or PI3Kd inhibitors (such asCAL-101/GS-1101, duvelisib), JNK inhibitors, ERK1 and/or 2 inhibitors,IKKb inhibitors, BTK inhibitors, ITK inhibitors, ASK1 inhibitors (suchas GS-4997), PKC inhibitors (such as sotrastaurin), TrkA antagonists(such as CT-327), MEK1 inhibitors (such as E6201);

Antioxidants, including but not limited to, myeloperoxidase inhibitors(such as AZD-3241), NOX4 and other NOX enzymes (such as GKT-137831) andN-acetyl cysteine;

Inhibitors of IL5, including but not limited to, mepolizumab, reslizumaband benralizumab;

Inhibitors of IL4, including but not limited to, pascolizumab,altrakincept and pitrakinra;

Inhibitors of IL13, including but not limited to, tralokinumab,anrukinzumab and lebrikizumab;

Anti-IL6 agents, including but not limited to, tocilizumab, olokizumab,siltuximab, PF-4236921 and sirukumab;

Inhibitors/Antagonists of IL17/IL17R, including but not limited to,secukinumab, RG-7624, brodalumab and ixekizumab;

Antagonists of IL12 and/or IL23, including but not limited to,tildrakizumab, guselkumab, MEDI2070 and AMG 139;

Inhibitors of IL33, including but not limited to, AMG 282;

Inhibitors of IL9, including but not limited to, MEDI-528;

Inhibitors of GM-CSF, including but not limited to, MT203;

Anti CD4 agents, including but not limited to, tregalizumab andrigerimod;

CRTH2 antagonists, including but not limited to, AZD-1981;

Inhibitors of B lymphocyte stimulator (BLYS; also known as BAFF), aprotein that is often increased in patients with SLE, including but notlimited to, belimumab, tabalumab, blisibimod, and atacicept;

CD22-specific monoclonal antibodies, including but not limited to,epratuzumab;

Inhibitors of interferon-α, including but not limited to, sifalimumaband rontalizumab;

Inhibitor of type I interferon receptors, including but not limited to,MEDI-546;

FcγRIIB agonists, including but not limited to, SM-101;

Modified and/or recombinant versions of Heat Shock Protein 10 (Hsp10,also known as Chaperonin 10 or EPF), including but not limited to,INV-103;

Inhibitors of the TNF superfamily receptor 12A (TWEAK receptor),including but not limited to, BIIB-023, enavatuzumab, and RG-7212;

Inhibitors of xanthine oxidase, including but not limited to,allopurinol, benzbromarone, febuxostat, topiroxostat, tisopurine andinositols;

Inhibitors of URAT1 (also known as SLC22A12), including but not limitedto, lesinurad, RDEA 3170, UR1102 and levotofispam;

Additional treatments for gout and/or lowering of uric acid levels,including but not limited to, colchicines, pegloticase, benziodarone,isobrominidione, BCX4208 and arhalofenate;

Inhibitors of toll-like receptors (TLRs), including but not limited to,one or more of TLR7, TLR8, TLR9 (such as IMO-8400, IMO-3100, DV-1179),TLR2 and/or TLR 4 (such as VB-201, OPN-305);

Agonists of TLRs, including but not limited to, TLR7 (such asGSK2245035, AZD8848), TLR9 (such as AZD1419);

Activators SIRT1, including but not limited to, SRT2104;

A3 receptor agonists, including but not limited to, CF101;

Other agents of use of the treatment of psoriasis, including but notlimited to, IDP-118, LAS41004, LEO 80185, LEO 90100, PH-10, WBI-1001,CNT01959, BT-061, cimzia, ustekinumab, MK-3222/SCH 900222, ACT-128800,AEB071, alitretinoin, ASPO15K, Apo805K1, BMS-582949, FP187, hectoral(doxercalciferol), LEO 22811, Ly3009104 (INCB28050), calcipotrene foam(STF 115469), tofactinib (CP-690,550), M518101 and CycloPsorb™;

Antifibrotic agents, including but not limited to: pirfenidone,inhibitors of LOXL2 (such as Simtuzumab), FT-011, modulators ofepiregulin and/or TGFα (such as LY-3016859), modulators of TGFβ (such asLY-2382770, fresolimumab);

Prolyl hydroxylase inhibitors, including but not limited to, GSK1278863,FG-2216, ASP-1517/FG-4592, AKB-6548, JTZ-951, BAY-85-3934 and DS-1093;

Inhibitors of granulocyte macrophage colony-stimulating factor,including but not limited to, GSK3196165 (MOR103), PD-0360324 andmavrilimumab;

Inhibitors of MAdCAM and/or α4P7 integrin, including but not limited to,PF-00547659 and MEDI7183 (abrilumab);

Inhibitors of connective tissue growth factor (CTGF), including but notlimited to, PF-06473871; Inhibitors of cathepsin C, including but notlimited to, GSK2793660;

Inhibitors of soluble epoxide hydrolase, including but not limited to,GSK2269557;

Inhibitors of the TNFR1 associated death domain protein, including butnot limited to, GSK2862277;

Anti-CD19 agents, including but not limited to, MEDI-551 and AMG 729;

Anti-B7RP1 agents/inhibitors of ICOS ligand, including but not limitedto, MED15872 and AMG-557;

Inhibitors of thymic stromal lymphoprotein, including but not limitedto, AMG157;

Inhibitors of IL2, including but not limited to, daclizumab;

Inhibitors of Leucine rich repeat neuronal protein 6A, including but notlimited to, Anti-Lingo (Biogen);

Inhibitors of integrins, including but not limited to, alpha-V/beta-6(STX-100) and alpha-V/beta-3 (VPI-2690B);

Anti-CD40 L agents, including but not limited to, CDP-7657;

Modulators of the dopamine D3 receptor, including but not limited to,ABT-614;

Inhibitors and/or modulators of galectin-3, including but not limitedto, GCS-100 and GR-MD-02;

Agents for treating diabetic nephropathy, including but not limited to,DA-9801 and ASP-8232;

Agents for treating acute kidney injury, including but not limited to,THR-184, TRC-160334, NX-001, EA-230, ABT-719, CMX-2043, BB-3 andMTP-131;

Modulators of inflammasomes, including but not limited to, inhibitors ofNLRP3;

Modulators of bromodomains, including but not limited to, BRD4;

Modulators of GPR43; and

Inhibitors of TRP channels, including but not limited to, TRPA1, TRPC3,TRPC5, TRPC6 and TRPC6.

Additional therapeutic agents include anti-coagulant or coagulationinhibitory agents, anti-platelet or platelet inhibitory agents, thrombininhibitors, thrombolytic or fibrinolytic agents, anti-arrhythmic agents,anti-hypertensive agents, calcium channel blockers (L-type and T-type),cardiac glycosides, diuretics, mineralocorticoid receptor antagonists,NO donating agents such as organonitrates, NO promoting agents such asphosphodiesterase inhibitors, cholesterol/lipid lowering agents andlipid profile therapies, anti-diabetic agents, anti-depressants,anti-inflammatory agents (steroidal and non-steroidal),anti-osteoporosis agents, hormone replacement therapies, oralcontraceptives, anti-obesity agents, anti-anxiety agents,anti-proliferative agents, anti-tumor agents, anti-ulcer andgastroesophageal reflux disease agents, growth hormone and/or growthhormone secretagogues, thyroid mimetics (including thyroid hormonereceptor antagonist), anti-infective agents, anti-viral agents,anti-bacterial agents, and anti-fungal agents.

Agents used in an ICU setting are included, for example, dobutamine,dopamine, epinephrine, nitroglycerin, nitroprusside, etc.

Combination agents useful for treating vasculitis are included, forexample, azathioprine, cyclophosphamide, mycophenolate, mofetil,rituximab, etc.

In another embodiment, the present invention provides a combinationwherein the second agent is at least one agent selected from a factor Xainhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombininhibiting agent, a thrombolytic agent, and a fibrinolytic agent.Exemplary factor Xa inhibitors include apixaban and rivaroxaban.Examples of suitable anti-coagulants for use in combination with thecompounds of the present invention include heparins (e.g., unfractionedand low molecular weight heparins such as enoxaparin and dalteparin).

In another embodiment the second agent is at least one agent selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac,sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban,eptifibatide, abciximab, melagatran, disulfatohirudin, tissueplasminogen activator, modified tissue plasminogen activator,anistreplase, urokinase, and streptokinase.

In another embodiment, the agent is at least one anti-platelet agent.Especially preferred anti-platelet agents are aspirin and clopidogrel.The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example byinhibiting the aggregation, adhesion or granular secretion of platelets.Agents include, but are not limited to, the various known non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,sulindac, indomethacin, mefenamate, droxicam, diclofenac,sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts orprodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA)and COX-2 inhibitors such as celecoxib or piroxicam are preferred. Othersuitable platelet inhibitory agents include IIb/IIIa antagonists (e.g.,tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptorantagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors,PDE-III inhibitors (e.g., Pletal, dipyridamole), and pharmaceuticallyacceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferably antagonists of the purinergic receptors P₂Y₁ andP₂Y₁₂, with P₂Y₁₂ being even more preferred. Preferred P₂Y₁₂ receptorantagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel,including pharmaceutically acceptable salts or prodrugs thereof.Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrelare also preferred compounds since they are known to be gentle on thegastro-intestinal tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin, argatroban, andmelagatran, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminalalpha-aminoboronic acid derivatives of lysine, ornithine, arginine,homoarginine and corresponding isothiouronium analogs thereof. The termhirudin, as used herein, includes suitable derivatives or analogs ofhirudin, referred to herein as hirulogs, such as disulfatohirudin. Theterm thrombolytics or fibrinolytic agents (or thrombolytics orfibrinolytics), as used herein, denote agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (natural orrecombinant) and modified forms thereof, anistreplase, urokinase,streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIlainhibitors, PAl-1 inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), alpha2-antiplasmin inhibitors, and anisoylatedplasminogen streptokinase activator complex, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in EP 028,489, the disclosure ofwhich is hereby incorporated herein by reference herein. The termurokinase, as used herein, is intended to denote both dual and singlechain urokinase, the latter also being referred to herein asprourokinase. Examples of suitable anti-arrythmic agents include: ClassI agents (such as propafenone); Class II agents (such as metoprolol,atenolol, carvadiol and propranolol); Class III agents (such as sotalol,dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (suchas ditiazem and verapamil); K⁺ channel openers such as I_(Ach)inhibitors, and I_(Kur) inhibitors (e.g., compounds such as thosedisclosed in WO01/40231).

The compounds of the present invention may be used in combination withantihypertensive agents and such antihypertensive activity is readilydetermined by those skilled in the art according to standard assays(e.g., blood pressure measurements). Examples of suitableanti-hypertensive agents include: alpha adrenergic blockers; betaadrenergic blockers; calcium channel blockers (e.g., diltiazem,verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine),diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, torsemide, furosemide, musolimine,bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors;ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutralendopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginalagent is ivabradine.

Examples of suitable calcium channel blockers (L-type or T-type) includediltiazem, verapamil, nifedipine and amlodipine and mybefradil. Examplesof suitable cardiac glycosides include digitalis and ouabain.

In one embodiment, a compound of the invention may be co-administeredwith one or more diuretics. Examples of suitable diuretics include (a)loop diuretics such as furosemide (such as LASIX™), torsemide (such asDEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such asEDECRIN™); (b) thiazide-type diuretics such as chlorothiazide (such asDIURIL™ ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (such asMICROZIDE™ or ORETIC™) benzthiazide, hydroflumethiazide (such asSALURON™), bendroflumethiazide, methychlorthiazide, polythiazide,trichlormethiazide, and indapamide (such as LOZOL™); (c)phthalimidine-type diuretics such as chlorthalidone (such as HYGROTON™),and metolazone (such as ZAROXOLYN™); (d) quinazoline-type diuretics suchas quinethazone; and (e) potassium-sparing diuretics such as triamterene(such as DYRENIUM™), and amiloride (such as MIDAMOR™ or MODURETIC™). Inanother embodiment, a compound of the invention may be co-administeredwith a loop diuretic. In still another embodiment, the loop diuretic isselected from furosemide and torsemide. In still another embodiment, oneor more compounds of the invention may be co-administered withfurosemide. In still another embodiment, one or more compounds of theinvention may be co-administered with torsemide which may optionally bea controlled or modified release form of torsemide.

In another embodiment, a compound of the invention may beco-administered with a thiazide-type diuretic. In still anotherembodiment, the thiazide-type diuretic is selected from the groupconsisting of chlorothiazide and hydrochlorothiazide. In still anotherembodiment, one or more compounds of the invention may beco-administered with chlorothiazide. In still another embodiment, one ormore compounds of the invention may be co-administered withhydrochlorothiazide. In another embodiment, one or more compounds of theinvention may be co-administered with a phthalimidine-type diuretic. Instill another embodiment, the phthalimidine-type diuretic ischlorthalidone.

Examples of suitable combination mineralocorticoid receptor antagonistsinclude sprionolactone and eplerenone. Examples of suitable combinationphosphodiesterase inhibitors include: PDE III inhibitors (such ascilostazol); and PDE V inhibitors (such as sildenafil).

The compounds of the present invention may be used in combination withcholesterol modulating agents (including cholesterol lowering agents)such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoAsynthase inhibitor, an HMG-CoA reductase gene expression inhibitor, anHMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretioninhibitor, a CETP inhibitor, a bile acid absorption inhibitor, acholesterol absorption inhibitor, a cholesterol synthesis inhibitor, asqualene synthetase inhibitor, a squalene epoxidase inhibitor, asqualene cyclase inhibitor, a combined squalene epoxidase/squalenecyclase inhibitor, a fibrate, niacin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid sequestrant or an agentsuch as mipomersen.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies include: HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin)); squalene synthetaseinhibitors; fibrates; bile acid sequestrants (such as questran); ACATinhibitors; MTP inhibitors; lipooxygenase inhibitors; cholesterolabsorption inhibitors; and cholesteryl ester transfer proteininhibitors.

Anti-inflammatory agents also include sPLA2 and IpPLA2 inhibitors (suchas darapladib), 5 LO inhibitors (such as atrelueton) and IL-1 and IL-1rantagonists (such as canakinumab).

Other atherosclerotic agents include agents that modulate the action ofPCSK9, for example, called bococizumab.

Cardiovascular complications of type 2 diabetes are associated withdeleterious levels of MPO, accordingly, the compounds of the presentinvention may be used in combination with anti-diabetic agents,particularly type 2 anti-diabetic agents. Examples of suitableanti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors,GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors)Suitable anti-diabetic agents include an acetyl-CoA carboxylase-(ACC)inhibitor such as those described in WO2009144554, W2003072197,WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1(DGAT-1) inhibitor, such as those described in WO09016462 orWO2010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2(DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, aphosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea(e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylaseinhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucosidehydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g.,adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,and salbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone androsiglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such asan agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide,exenatide (Byetta@), albiglutide, lixisenatide, dulaglutide,semaglutide, NN-9924, TTP-054, a protein tyrosine phosphatase-1B(PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, andcompounds disclosed by Zhang, S., et al., Drug Discovery Today,12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol,GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor(e.g., those in W2005116014, sitagliptin, vildagliptin, alogliptin,dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, afatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminalkinase (JNK) inhibitor, glucokinase activators (GKa) such as thosedescribed in WO2010103437, WO2010103438, WO2010013161, WO2007122482,TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors,such as those described in E. C. Chao et al. Nature Reviews DrugDiscovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin,empagliflozin, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071,ISIS388626 and LX4211 as well as those in WO2010023594, a glucagonreceptor modulator such as those described in Demong, D. E. et al.Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119modulators, particularly agonists, such as those described inWO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R. M. etal. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263,APD597 and PSN821), FGF21 derivatives or analogs such as those describedin Kharitonenkov, A. et al. et al., Current Opinion in InvestigationalDrugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators,particularly agonists, such as those described in Zhong, M., CurrentTopics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40agonists, such as those described in Medina, J. C., Annual Reports inMedicinal Chemistry, 2008, 43, 75-85, including but not limited toTAK-875, GPR120 modulators, particularly agonists, high affinitynicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, suchas GSK1614235. A further representative listing of anti-diabetic agentsthat can be combined with the compounds of the present invention can befound, for example, at page 28, line 35 through page 30, line 19 ofWO2011005611. Preferred anti-diabetic agents are metformin and DPP-IVinhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin,linagliptin and saxagliptin). Other antidiabetic agents could includeinhibitors or modulators of carnitine palmitoyl transferase enzymes,inhibitors of fructose 1,6-diphosphatase, inhibitors of aldosereductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2,inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa,PKCp, PKC), inhibitors of fatty acid synthetase, inhibitors of serinepalmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105,Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostainreceptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulatorsof PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 familyincluding IL1beta, modulators of RXRalpha. In addition suitableanti-diabetic agents include mechanisms listed by Carpino, P. A.,Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

Those skilled in the art will recognize that the compounds of thisinvention may also be used in conjunction with other cardiovascular orcerebrovascular treatments including PCI, stenting, drug eluting stents,stem cell therapy and medical devices such as implanted pacemakers,defibrillators, or cardiac resynchronization therapy.

The compounds of the present invention may be used in combination withneuroinflammatory and neurodegenerative agents in mammals. Examples ofadditional neuroinflammatory and neurodegenerative agents includeantidepressants, antipsychotics, anti-pain agents, anti-Alzheimer'sagents, and anti-anxiety agents. Examples of particular classes ofantidepressants that can be used in combination with the compounds ofthe invention include norepinephrine reuptake inhibitors, selectiveserotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists,monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRs),corticotropin releasing factor (CRF) antagonists, and atypicalantidepressants. Suitable norepinephrine reuptake inhibitors includetertiary amine tricyclics and secondary amine tricyclics. Examples ofsuitable tertiary amine tricyclics and secondary amine tricyclicsinclude amitriptyline, clomipramine, doxepin, imipramine, trimipramine,dothiepin, butriptyline, nortriptyline, protriptyline, amoxapine,desipramine and maprotiline. Examples of suitable SSRIs includefluoxetine, fluvoxamine, paroxetine, and sertraline. Examples ofmonoamine oxidase inhibitors include isocarboxazid, phenelzine, andtranylcyclopramine. Examples of suitable reversible inhibitors ofmonoamine oxidase include moclobemide. Examples of suitable SNRIs of usein the present invention include venlafaxine. Examples of suitableatypical anti-depressants include bupropion, lithium, trazodone andviloxazine. Examples of anti-Alzheimer's agents include NMDA receptorantagonists such as memantine; and cholinesterase inhibitors such asdonepezil and galantamine. Examples of suitable classes of anti-anxietyagents that can be used in combination with the compounds of theinvention include benzodiazepines and serotonin 1A receptor (5-HT1A)agonists, and CRF antagonists. Suitable benzodiazepines includealprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,lorazepam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonistsinclude buspirone and ipsapirone. Suitable CRF antagonists includeverucerfont.

Suitable atypical antipsychotics include paliperidone, ziprasidone,risperidone, aripiprazole, olanzapine, and quetiapine. Suitable nicotineacetylcholine agonists include CP-601927 and varenicline. Anti-painagents include pregabalin, gabapentin, clonidine, neostigmine, baclofen,midazolam, ketamine and ziconotide.

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of the invention.

The present invention further comprises intermediate compounds useful inthe synthesis of the compounds of the invention, including salts and/ortautomers thereof.

General Synthetic Schemes

The compounds of Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and transformations that are familiar tothose of ordinary skill in the art. The starting materials used hereinare commercially available or may be prepared by routine methods knownin the art [such as those methods disclosed in standard reference bookssuch as the Compendium of Organic Synthetic Methods, Vol. I-XII(published by Wiley-Interscience)]. Preferred methods include, but arenot limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991; and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999, which are herebyincorporated by reference.

Compounds of Formula I, or their pharmaceutically acceptable salts, canbe prepared according to the reaction Schemes discussed herein below.Unless otherwise indicated, the substituents in the Schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the schemes, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the schemes, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. Additionally, one skilled in the artwill recognize that in many cases, these compounds will be mixtures andenantiomers that may be separated at various stages of the syntheticschemes using conventional techniques, such as, but not limited to,crystallization, normal-phase chromatography, reversed phasechromatography and chiral chromatography, to afford single enantiomers.The schemes are representative of methods useful in synthesizing thecompounds of the present invention. They are not to constrain the scopeof the invention in any way.

Scheme 1 illustrates a method for preparing compounds of Formula Ia. Acompound of Formula A, in which Lv is a displaceable leaving group (suchas chloro or fluoro, for example) is treated with a compound of FormulaB (for example, see Scheme 9, or as commercially available) to furnish aproduct of Formula Ia. The reaction is typically carried out in thepresence of a suitable base such as cesium carbonate, potassiumtert-butoxide, sodium hydride or potassium hexamethyldisilazide in asuitable solvent or solvent mixture, such as THF or dimethylformamide.The compounds of Formula A may be prepared as described in thesubsequent schemes. The compounds of formula R²—OH may be obtained fromcommercial vendors, or prepared by methods reported in the chemicalliterature, or may be prepared as described in the subsequent schemes.

If desired, further transformations may be effected upon the compound ofFormula Ia. For example, the compound of Formula Ia wherein R⁶=CN may besubjected to a nitrile hydrolysis reaction to provide a compound ofFormula Ia in which R⁶=CONH₂. The reaction may be carried out in avariety of ways known to one skilled in the art, for example by the useof acids or bases, optionally in the presence of an oxidant such ashydrogen peroxide, or by using chemical or enzymatic catalysts. In othercases, the compound of Formula Ia may be further treated with reagents,such as acids, to cleave protecting groups, such as t-butoxycarbonylgroups, and/or with other reagents to derivatize functional groups suchas carboxyl, amino, or hydroxyl groups.

Scheme 2 illustrates another method for the preparation of compounds ofFormula Ia, particularly suited to those instances in which X and Y inthe compound of Formula A are both carbon. This method provides for thealkylation of a compound of Formula A with a compound of Formula B(wherein the R¹²O— group is either hydroxyl or a sulfonate ester such asp-toluenesulfonate or methanesulfonate; for example, see Scheme 9, or ascommercially available), using methods known to those skilled in theart, to furnish a product of Formula Ia. For example, this reaction maybe carried out by treating a compound of Formula A with a compound ofFormula B (R¹²=H) in the presence of triphenylphosphine and anazodicarboxylate ester (“Mitsunobu reaction”) in a suitable solvent suchas THF. Alternatively, the alkylation of a compound of Formula A may beeffected using a compound of Formula B (R¹²O=TsO or other sulfonateester) in the presence of a base such as cesium carbonate, in a suitablesolvent such as THF or dimethylformamide.

If desired, further transformations may be effected upon the compound ofFormula Ia. For example, the compound of Formula Ia wherein R⁶=CN may besubjected to a nitrile hydrolysis reaction to provide a compound ofFormula Ia in which R⁶=CONH₂. The reaction may be carried out in varietyof ways known to one skilled in the art, for example by the use of acidsor bases, optionally in the presence of an oxidant such as hydrogenperoxide, or by using chemical or enzymatic catalysts. In other cases,the compound of Formula Ia may be further treated with reagents, such asacids, to cleave protecting groups, such as t-butoxycarbonyl groups,and/or with other reagents to derivatize functional groups such ascarboxyl, amino, or hydroxyl groups.

Scheme 3 illustrates a method for the preparation of compounds ofFormula A, wherein Y=N and X=CH, as illustrated above. An acid ofFormula Ci is treated with an alkylating agent, for example, iodomethane(R¹=methyl), and a base, such as K₂CO₃, in a suitable solvent such asDMF. The resulting ester of Formula Cii is then reduced to a compound ofFormula Ciii by treatment with a suitable reducing agent, such as NaBH₄,in a solvent such as THF. The alcohol of Formula Ciii is oxidized to analdehyde of Formula Civ using methods known to those skilled in the art,such as treatment with pyridinium chlorochromate or manganese dioxide.The isoquinoline ring is formed from the aldehyde of Formula Civ byreaction with an aminoacetaldehyde acetal followed by treatment withboron trifluoride etherate, as described in Synthetic Communications1999, 29 (9), p. 1617. The resulting isoquinoline of Formula Cv iscyanated, using methods known to those skilled in the art, such astreatment with copper(I) cyanide in a solvent such as DMF or pyridine,to afford a nitrile of Formula Cvi. Oxidation with a suitable oxidizingagent, such as hydrogen peroxide or a peracid such as m-chloroperbenzoicacid or peracetic acid, yields an isoquinoline N-oxide of Formula Cvii.This may be halogenated by methods known to those skilled in the art,frequently by treatment with phosphorus oxychloride with or without anadditional solvent, to afford the intermediate of Formula A (Lv=Cl).

Scheme 4 illustrates a method for the preparation of compounds ofFormula A wherein Y=N and X=CH. An aldehyde of Formula Cviii is treatedwith an alkylating agent, for example, 2-bromopropane (R¹=isopropyl),and a base such as K₂CO3 in a suitable solvent such as DMF or DMSO. Thealdehyde of Formula Cix is then subjected to Knoevenagel condensationwith malonic acid, typically in the presence of pyridine and piperidine,to afford an acid of Formula Cx. The acid may be converted to an acylazide of Formula Cxi by a variety of means known to one skilled in theart, for example by sequential treatment with a chloroformate esterfollowed by reaction with sodium azide. Upon exposure to heat, the acylazide may undergo Curtius reaction to ultimately afford a compound ofFormula Cxii. The Curtius reaction may be effected in a suitablesolvent, for example diphenyl ether, at a temperature typically inexcess of 200° C. The compound of Formula Cxii is cyanated, usingmethods known to those skilled in the art, such as treatment with zinccyanide under palladium catalysis, to afford a compound of FormulaCxiii. This may be halogenated by methods known to those skilled in theart, frequently by treatment with phosphorus oxychloride with or withoutan additional solvent, to afford the intermediate of Formula A (Y=N,X=CH, Lv=Cl).

Scheme 5 illustrates a method for the preparation of compounds ofFormula A wherein X and Y=N. An ester of Formula Cxiv is nitrated withnitric acid to afford a compound of Formula Cxv, which may then bereduced to an amine of Formula Cxvi by methods known to those skilled inthe art, for example by treatment with tin(II) chloride in acidsolution. Subsequent treatment with formamide or similar reagents may beused to effect formation of a quinazolinone of Formula Cxvii. Theresulting quinazolinone of Formula Cxvii is cyanated, using methodsknown to those skilled in the art, such as treatment with zinc cyanideand a palladium catalyst such as tetra(kis)triphenylphosphinepalladium(0), in a solvent such as THF to afford a nitrile of FormulaCxviii. This may be halogenated by methods known to those skilled in theart, frequently by treatment with phosphorus oxychloride with or withoutan additional solvent, to afford the intermediate of Formula A (Lv=Cl).

Scheme 6 illustrates a method for the preparation of compounds ofFormula A. A nitrobenzoate ester of Formula Cxix is reduced by methodsknown to those skilled in the art, for example by hydrogen in thepresence of a palladium catalyst in a solvent such as ethanol, to anamine of Formula Cxx. This amine is condensed with a malonic acidderivative such as Meldrum's acid in the presence of a trialkylorthoformate, such as triethyl orthoformate, in a suitable solvent suchas ethanol to afford a compound of Formula Cxxi. Thermal cyclization iseffected by heating a compound of Formula Cxxi to a temperaturetypically in excess of 200° C., and typically in a solvent such asdiphenyl ether or Dowtherm A, to afford a quinolone of Formula Cxxii, insome cases accompanied by the regioisomer of Formula Cxxiii. Separationof these isomers may be accomplished by selective saponification with analkali, for example lithium hydroxide, in a solvent such as aqueous THFto afford the desired quinolone of Formula Cxxiv. This compound may behalogenated by methods known to those skilled in the art, frequently bytreatment with phosphorus oxychloride with or without an additionalsolvent. The carboxylic acid may then be converted to the carboxamide bymethods known to those skilled in the art; for example, by treatmentwith an excess of ammonia in a reaction compatible solvent such as1,4-dioxane affords the intermediate of Formula A.

Scheme 7 illustrates a method for the preparation of compounds ofFormula A wherein X and Y are both carbon. A naphthol of Formula Cxxvmay be subjected to Fischer esterification to afford a compound ofFormula Cxxvi. The distal hydroxyl group may be masked using a suitableprotecting group (PG), for example, by forming a silyl ether usingstandard conditions known to one skilled in the art, for example witht-butyldiphenylsilyl chloride and imidazole, in a suitable solvent suchas 1,2-dichloroethane, to provide a compound of Formula Cxxvii.Alkylation of the proximal hydroxyl group may be carried out with analcohol R¹—OH in the presence of triphenylphosphine and anazodicarboxylate ester (“Mitsunobu reaction”) in a suitable solvent suchas THF to furnish a compound of Formula Cxxviii, which may be saponifiedby an alkali to afford a compound of Formula Cxxix. Conversion to theprimary amide may be accomplished using standard methods known to oneskilled in the art, for example by way of conversion to an acyl chlorideusing a reagent such as oxalyl chloride to afford a compound of FormulaCxxx, which may be converted to the primary amide of Formula A, bymethods known to those skilled in the art; for example, by exposure toan excess of ammonia, typically in the presence of a suitable solventsuch as THF, water, or a mixture of solvents.

Scheme 8 illustrates a method for the preparation of additionalcompounds of Formula A. In this method, a compound of Formula A isdealkylated to remove the R¹ alkyl group to afford a compound of FormulaAi. Dealkylation may be effected by standard methods known to oneskilled in the art, for example by the use of anhydrous aluminumchloride or boron tribromide in a solvent such as DCM, and may be mostadvantageously effected when R⁶=CN. Subsequent alkylation of the OHgroup may be effected to install a new R¹ group to afford a new compoundof Formula A, using methods known to one skilled in the art, for exampleby treatment with an alcohol R¹—OH in the presence of triphenylphosphineand an azodicarboxylate ester (“Mitsunobu reaction”) in a suitablesolvent such as THF, or by treatment with an alkylating agent such as analkyl chloride, bromide, or iodide (R¹—Cl, R¹—Br, or R¹—) and a basesuch as K₂CO3 in a suitable solvent such as THF or DMF.

Scheme 9 illustrates a method for the preparation of certain compoundsof Formula B of the type R²—OH as employed in Schemes 1 and 2. Compoundsof Formula Cxxxi are well known in the chemical literature, particularlythose compounds in which R_(a) and R_(b) are both methyl, and in whichR_(a) is (substituted)phenyl and R_(b) is H. In this method, thecompound of Formula Cxxxi is treated with a suitable base, frequentlylithium hexamethyldisilazide or lithium diisopropylamide, in a suitablesolvent such as THF, ether, MTBE or 2-methylTHF using conditionswell-established in the chemical literature. The mixture may then betreated with an electrophile to install the electrophile E₁ on thelactam ring. Suitable electrophiles are well known to those skilled inthe art and include, but are not limited to, halogenating agents such aselectrophilic halogen species, alkylating agents such as alkyl halides,carbonyl compounds such as aldehydes, ketones, or esters, oxidizingagents such as molecular oxygen or sulfonyloxaziridines, aminatingagents such as sulfonyl azides, and sulfur containing electrophiles suchas disulfides, thiocyanates, sulfinates, and sulfonyl halides. Theresulting substituted lactam of Formula Cxxxii may be subjected to thisprocess a second time to install another electrophile on the lactamring, designated in the scheme by E₂. It will be recognized by oneskilled in the art that the electrophiles E₁ and E₂ may themselves besubjected to further chemical transformations. It will also berecognized that the introduction of the electrophiles E₁ and E₂ maygenerate a mixture of stereoisomers, which may be separated by knownmethods into discrete stereoisomerically pure compounds. Finally,treatment with an acid is commonly used to remove the aminal protectinggroup containing R_(a) and R_(b) to afford the R₂—OH compound of FormulaB. It will also be recognized that the electrophiles E₁ and E₂ willultimately afford the substituents R⁴ in the compound of Formula Ia.

Scheme 10 illustrates a method for the preparation of certain compoundsof the type R²—OH as employed in Schemes 1 and 2. In this method, thecompound of Formula Cxxxi is oxidized to the olefin compound of FormulaCxxxiv using methods that are known in the chemical literature. This isfrequently accomplished by the elimination reaction of a sulfoxide orselenoxide, or it may be carried out by treatment with a suitable basesuch as lithium diisopropylamide and chlorotrimethylsilane followed byoxidation of the resulting silyl ketene aminal with a palladium salt anda carbonate ester of allyl alcohol, in a transformation known to oneskilled in the art as the Saegusa—Tsuji oxidation. The olefin of FormulaCxxxiv may be converted to a compound of Formula Cxxxv using methodsthat are known in the chemical literature, frequently by treatment withan organometallic reagent such as methyllithium (R_(c)=methyl) orethylmagnesium chloride (R_(c)=ethyl) in the presence ofchlorotrimethylsilane and a copper compound. The compound of FormulaCxxxv may then be treated with an electrophile, designated in Scheme 10by E₁, to install the electrophile E₁ on the lactam ring as describedpreviously in Scheme 9. Likewise, the resulting compound of FormulaCxxxvi may be subjected to this process a second time to install anotherelectrophile on the lactam ring, designated in Scheme 10 by E₂. It willbe recognized by one skilled in the art that the electrophiles E₁ andE₂, and the R, group, may themselves be subjected to further chemicaltransformations. It will also be recognized that the introduction of theR, group and the electrophiles E₁ and E₂ may generate a mixture ofstereoisomers, which may be separated into discrete stereoisomericallypure compounds. As in Scheme 9, treatment with an acid is commonly usedto remove the aminal protecting group containing R_(a) and R_(b) toafford the R²—OH compound of Formula B. It will also be recognized thatthe R, group and the electrophiles E₁ and E₂ will ultimately afford thesubstituents R⁴ in the compound of Formula Ia.

Scheme 11 illustrates a method for the preparation of certain compoundsof the type R²—OH as employed in Schemes 1 and 2. In this method, theolefin compound of Formula Cxxxiv is subjected to cyclopropanation usingmethods that are known in the chemical literature, frequently bytreatment with an appropriately substituted sulfonium salt and asuitable base. It will be recognized by one skilled in the art that theR_(d) and R_(e) groups may be subjected to further chemicaltransformations. It will also be recognized that the introduction of thecyclopropane ring containing the R_(d) and R_(e) groups may generate amixture of stereoisomers, which may be separated by known methods intodiscrete stereoisomerically pure compounds. As in Scheme 9, treatmentwith an acid is commonly used to remove the aminal protecting groupcontaining R_(a) and R_(b) to afford the R²—OH compound of Formula B. Itwill also be recognized that the cyclopropane ring containing the R_(d)and R_(e) groups will ultimately afford the substituents R⁴ in thecompound of Formula Ia.

Scheme 12 illustrates a method for the preparation of certain compoundsof the type R²—OH as employed in Schemes 1 and 2. In this method, theolefin of Formula Cxxxix bearing suitable protecting groups PG₁ and PG₂,wherein PG₁ is, for example, a carbamate such as t-butyl carbamate andPG₂, for example, is a trialkylsilyl such as TBDMS, may be converted toa compound of Formula Cxl using methods that are known in the chemicalliterature. This is frequently accomplished by treatment with anorganometallic reagent such as methyllithium (R_(c)=methyl) orethylmagnesium chloride (R_(c)=ethyl) in the presence ofchlorotrimethylsilane and a copper compound. The compound of Formula Cxlmay then be treated with an electrophile (E₁), to install theelectrophile E₁ on the lactam ring as described previously in Scheme 9.Likewise, the resulting compound of Formula Cxli may be subjected tothis process a second time to install another electrophile (E₂). It willbe recognized by one skilled in the art that the electrophiles E₁ andE₂, and the R_(c) group, may themselves be subjected to further chemicaltransformations. It will also be recognized that the introduction of theR_(c) group and the electrophiles E₁ and E₂ may generate a mixture ofstereoisomers, which may be separated by known methods into discretestereoisomerically pure compounds. As in Scheme 9, treatment with anacid is commonly used to remove the aminal protecting group containingR_(a) and R_(b) to afford the R²—OH compound of Formula B. It will alsobe recognized that the R_(c) group and the electrophiles E₁ and E₂ willultimately afford the substituents R⁴ in the compound of Formula Ia.

Scheme 13 illustrates a method for the preparation of certain compoundsof the type R²—OH as employed in Schemes 1 and 2. In this method, thecompound of Formula Cxxxi is treated with a suitable base, followed byan electrophile (E₁), to install the electrophile E₁ on the lactam ring,as described previously in Scheme 9. The compound of Formula Cxliii isoxidized to an olefin compound of Formula Cxliv using methods that areknown in the chemical literature, as described previously in Scheme 10.The olefin compound of Formula Cxliv is subjected to cyclopropanation,as described previously in Scheme 11. It will be recognized by oneskilled in the art that the E₁, R_(d) and R_(e) groups may be subjectedto further chemical transformations. It will also be recognized that theintroduction of the cyclopropane ring containing the E₁, R_(d) and R_(e)groups may generate a mixture of stereoisomers, which may be separatedby known methods into discrete stereoisomerically pure compounds. As inScheme 9, treatment with an acid is commonly used to remove the aminalprotecting group containing R_(a) and R_(b) to afford the R²—OH compoundof Formula B. It will also be recognized that the cyclopropane ringcontaining the E₁, R_(d) and R_(e) groups will ultimately afford thesubstituents R⁴ in the compound of Formula Ia.

Scheme 14 illustrates a method for the preparation of certain compoundsof the type R²—OH as employed in Schemes 1 and 2. In this method, theolefin compound of Formula Cxxxi is converted to a compound of FormulaCxxxv using methods that are known in the chemical literature asdescribed previously in Scheme 10. The compound of Formula Cxxxv isoxidized to an olefin compound of Formula Cxlvi using methods that areknown in the chemical literature as described previously in Scheme 10.The olefin compound of Formula Cxxxv is subjected to cyclopropanation asdescribed previously in Scheme 11. It will be recognized by one skilledin the art that the R_(c), R_(d) and R_(e) groups may be subjected tofurther chemical transformations. It will also be recognized that theintroduction of the cyclopropane ring containing the R_(c), R_(d) andR_(e) groups may generate a mixture of stereoisomers, which may beseparated by known methods into discrete stereoisomerically purecompounds. As in Scheme 9, treatment with an acid is commonly used toremove the aminal protecting group containing R_(a) and R_(b) to affordthe R²—OH compound of Formula B. It will also be recognized that thecyclopropane ring containing the R_(c), R_(d) and R_(e) groups willultimately afford the substituents R⁴ in the compound of Formula Ia.

Scheme 15 illustrates a method for the preparation of certain compoundsof the type R²—OH as employed in Schemes 1 and 2. In this method, theolefin of Formula Cxxxi may be converted to a compound of FormulaCxlviii using methods that are known in the chemical literature,frequently by treatment with an olefin reagent such as ethylene orpropylene under irradiation by ultraviolet light in a suitable solventsuch as acetone. It will be recognized by one skilled in the art thatthe R_(f), R_(g), R_(h) and R_(i) groups may be subjected to furtherchemical transformations. It will also be recognized that theintroduction of the cyclobutane ring containing the R_(f), R_(g), R_(h)and R_(i) groups may generate a mixture of stereoisomers, which may beseparated by known methods into discrete stereoisomerically purecompounds. As in Scheme 9, treatment with an acid is commonly used toremove the aminal protecting group containing R_(a) and R_(b) to affordthe R²—OH compound of Formula B. It will also be recognized that thecyclobutane ring containing the R_(f), R_(g), R_(h) and R_(i) groupswill ultimately afford the substituents R⁴ in the compound of FormulaIa.

Experimental Procedures and Working Examples

The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

It will be understood that the intermediate compounds of the inventiondepicted above are not limited to the particular enantiomer shown, butalso include all stereoisomers and mixtures thereof. It will also beunderstood that compounds of Formula Ia can include intermediates ofcompounds of Formula Ia.

Experimental Procedures

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification, includinganhydrous solvents where appropriate (generally Sure-Sea™ products fromthe Aldrich Chemical Company, Milwaukee, Wis.). Products were generallydried under vacuum before being carried on to further reactions orsubmitted for biological testing. Mass spectrometry data is reportedfrom either liquid chromatography-mass spectrometry (LCMS), atmosphericpressure chemical ionization (APCI) or gas chromatography-massspectrometry (GCMS) instrumentation. Chemical shifts for nuclearmagnetic resonance (NMR) data are expressed in parts per million (ppm,δ) referenced to residual peaks from the deuterated solvents employed.

For syntheses referencing procedures in other Examples or Methods,reaction conditions (length of reaction and temperature) may vary. Ingeneral, reactions were followed by thin layer chromatography and/orliquid chromatography-mass spectrometry, and subjected to work-up whenappropriate. It will be recognized by one skilled in the art thatpurifications may vary between experiments: in general, sorbents,solvents and the solvent ratios used for eluants/gradients were chosento provide appropriate R_(f)s or retention times. It will also berecognized by one skilled in the art that HPLC purifications may beeffected in a variety of ways, including the use of normal stationaryphases, reverse stationary phases, chiral stationary phases, andsupercritical eluants. The appropriate choices of conditions forchromatographic and HPLC purifications will be discerned by one skilledin the art.

The following Preparations describe the preparation of certainintermediates used in the Methods and Examples that follow. Thefollowing Preparations, Methods and Examples are intended to illustrateparticular embodiments of the invention and preparations thereto and arenot intended to limit the specification, including the claims, in anymanner. Unless noted otherwise, all reactants were obtainedcommercially.

Unless indicated otherwise, the following abbreviations have theindicated meanings:

APCI—atmospheric pressure chemical ionization

br.—broad peaks

° C.—degree Celsius

CDCl₃—deuterated chloroform

CD₃OD—deuterated methanol

d—doublet peak

dd—double doublet peak

D₂O—deuterium oxide

dmso-d₆—perdeuterated dimethyl sulfoxide

dt—double triplet peak

g—gram(s)

H (e.g., 1H, 2H)—hydrogen(s)

hr—hour(s)

LC—liquid chromatography

m—multiplet

M—molarity

mg—milligram(s)

MHz—megahertz

min—minute(s)

mL—milliliter(s)

mmol—millimole(s)

mp—melting point

MS—mass spectrum

NMR—nuclear magnetic resonance

pH—negative logarithm of hydronium ion concentration

psi—pounds per square inch

q—quartet peak

s—singlet peak

t—triplet peak

td—triple doublet peak

μL—microliter

Unless indicated otherwise, the following chemical formulas and acronymshave the indicated meanings:

AcOH—glacial acetic acid

BF₃-Et₂O—boron trifluoride etherate

BHT—2,6-dit-t-butyl-4-methylphenol

CHCl₃— chloroform

DAST—(diethylamino)sulfur trifluoride

DCM—dichloromethane

DMAP—(4-dimethylamino)pyridine

DMF—dimethylformamide

DMSO—dimethylsulfoxide

EDCl—N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

Et₃N—triethylamine

EtOAc—ethyl acetate

EtOH—ethanol

HCl—hydrochloric acid

HNO₃— nitric acid

H₂SO₄— sulfuric acid

H₃PO₄— phosphoric acid

LDA—lithium diisopropylamide

MeCN—acetonitrile

MeOH—methanol

MgSO₄— anhydrous magnesium sulfate

K₂CO3—potassium carbonate

K₃PO₄— anhydrous tribasic potassium phosphate

KOH—potassium hydroxide

MTBE—methyl t-butyl ether

Na₂CO3—sodium carbonate

Na₂SO₄— anhydrous sodium sulfate

NaBH₄— sodium borohydride

NaHCO₃— sodium bicarbonate

NaOH—sodium hydroxide

NFSI—N-fluoro(bisbenzenesulfonyl)imide, CAS 133745-75-2

NH₄Cl—ammonium chloride

POCl₃— phosphorus oxychloride

TFA—trifluoroacetic acid

THF—tetrahydrofuran

TMSCl—chlorotrimethylsilane

Preparations Preparation 1:1-chloro-7-methoxyisoquinoline-6-carbonitrile (P1) Step 1. Synthesis ofmethyl 4-iodo-3-methoxybenzoate (CAS 35387-92-9, C1)

To a solution of 3-hydroxy-4-iodobenzoic acid (CAS 58123-77-6, C12)(10800 g, 40.9 moles) in DMF (65 L) was added K₂CO3 (25398 g, 184moles), followed by the slow addition of dimethyl sulfate (11352 g, 90moles). This mixture was heated to about 50° C. for over night. Thereaction mixture was cooled to about 25° C., diluted with EtOAc (50 L)and filtered through a plug of Celite®. The solid was thoroughly washedwith EtOAc (10 L×3). The combined EtOAc filtrates were poured intowater. After stirring for about 30 min, the EtOAc layer was separatedand it was further washed sequentially with water, 1 M NaOH and brine.The EtOAc layer was separated, dried over Na₂SO₄, filtered andconcentrated to provide the title compound C1. Yield: 11750 g (98%).

Step 2. Synthesis of (4-iodo-3-methoxyphenyl)methanol (CAS 244257-61-2,C2)

To a solution of compound C1 (11750 g, 40.2 moles) in THF (35 L) wasadded NaBH₄ (7645 g, 201.09 moles) and refluxed. While refluxing, MeOH(25 L) was slowly added into the reaction mixture at a rate of about 1 Lper hour. After completion of the reaction, it was poured into asolution of cold dilute HCl. Once the excess of NaBH₄ was quenched, thesolution was filtered and extracted with EtOAc (2.5 L X 3). The combinedEtOAc extracts were washed sequentially with water, brine and dried overNa₂SO₄. The solvent was evaporated under reduced pressure and theresulting crude material was treated with MTBE. The resulting solid wasfiltered and filtrate was washed with water, brine, dried over Na₂SO₄,and filtered. The solvent was evaporated under reduced pressure toprovide the title compound C2. Yield: 9900 g (93%).

Step 3. Synthesis of 4-iodo-3-methoxybenzaldehyde (CAS 121404-83-9, C3)

To a solution of compound C2 (9900 g, 34.5 moles) in CHCl₃ (186 L), wasadded manganese dioxide (18000 g, 207 moles) and the resulting mixturewas refluxed for about 16 h. The mixture was cooled to about 25° C. andfiltered through a Celite pad, which was then washed thoroughly withCHCl₃. The CHCl₃ was evaporated under reduced pressure to provide thetitle compound C3. Yield: 9330 g (95%). ¹H NMR (400 MHz, CDCl₃): δ 9.95(s, 1H), 7.99 (d, 1H), 7.14 (dd, 1H), 3.95 (s, 3H).

Step 3. Synthesis of 6-iodo-7-methoxyisoquinoline (CAS 244257-63-4, C4)

To a solution of compound C3 (9300 g, 35 moles) in toluene (60 L) wasadded amino acetaldehyde dimethyl acetal (5590 g, 53 moles) and themixture was refluxed for about 4 h, while removing the liberated waterby the use of a Dean—Stark water separator. The reaction mixture wascooled to about 0° C., after which trifluoroacetic anhydride (22305 g,106 moles) followed by BF₃-Et₂O (15080 g, 106 moles) were added, keepinginternal temperature below 5° C. The reaction mixture was stirred atabout 25° C. for about 16 h and quenched by pouring into a mixture ofice and ammonium hydroxide. The product was extracted with EtOAc (10 L X3), and the combined EtOAc extracts were washed sequentially with waterand brine. The combined EtOAc extracts were dried over Na₂SO₄, filtered,and concentrated to afford a dark tan colored residue. This was treatedwith a mixture of MTBE and hexane (1:1 v/v, 30 L), followed by 6 M HCl(9 L), with stirring. The precipitated solid was filtered and washedwith MTBE. The solid was suspended in EtOAc (5 L) and made alkaline withammonium hydroxide. The EtOAc layer was separated, washed with brine,dried over Na₂SO₄, filtered, and concentrated to afford crude compoundC4 as a brown solid. HPLC (230 nm) showed it to be about 83% pure.

The crude material (1000 g) was taken in AcOH (2.5 L) and stirred forabout 90 min at about 25° C. The solid was filtered and washed with AcOH(500 mL). The filtrate was neutralized with saturated aqueous Na₂CO3solution. The resulting precipitated solid was filtered, washed withwater (4 L), and oven dried at about 70-75° C. for about 5 h to affordabout 780 g of pure C4. Similarly, the remaining crude C4 (4 kg) waspurified to provide the title compound C4. Yield: 4300 g (42%). ¹H NMR(400 MHz, CDCl₃): δ 9.15 (s, 1H), 8.45 (d, 1H), 8.35 (s, 1H), 7.45 (d,1H), 7.15 (s, 1H) 4.00 (s, 3H).

Step 4. Synthesis of 7-methoxyisoquinoline-6-carbonitrile (C5)

To a solution of compound C4 (4300 g, 15 moles) in DMSO (39 L) was addedcopper(I) cyanide (2954 g, 33 moles) and the mixture was heated to about120° C. for about 3 h. The reaction mixture was quenched by pouring intoa mixture of ice and ammonium hydroxide (40 L) and filtered. Thefiltrate was extracted with EtOAc (10 L×2). While stirring, the solidresidue was again treated with ammonium hydroxide solution (10 L) andEtOAc (10 L). After filtration, the precipitated material was repeatedlywashed with a mixture of MeOH and CHCl₃ (1:9, v/v) several times and thecombined extracts were washed with brine. The extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingcrude material was triturated with hexane to provide the title compoundC5. Yield: 2250 g (87%). ¹H NMR (400 MHz, CDCl₃): δ 9.25 (br. s, 1H),8.55 (br. s, 1H), 8.15 (s, 1H), 7.60 (d, 1H), 7.30 (s, 1H), 4.05 (s,3H).

Step 5. Synthesis of 7-methoxyisoquinoline-6-carbonitrile N-oxide (C6)

To a solution of compound C5 (500 g, 2.7 moles) in DCM (5 L) was slowlyadded 30% peracetic acid (413 g, 5.4 moles, 2 equivalents) at about40-45° C. over about 4 h. The resulting mixture was stirred at sametemperature for about 16 h. At this stage, 50% of starting material wasconsumed, and for further conversion another 2 equivalents of peraceticacid was added. The reaction mixture was heated at about 40-45° C. andmonitored by TLC. After approximately another 8 h, a trace of startingmaterial still remained. An additional 0.5 equivalent of peracetic acidwas added and the reaction was continued for about 5 h. Theheterogeneous reaction mass was cooled to about 25° C. and filtered. Theresulting solid was washed with water (2 L X 3) and subsequentlytriturated with acetone (2 L). Upon drying, 250 g of compound C6 wasobtained.

The DCM layer resulting from the filtration was washed with saturatedaqueous NaHCO₃ solution (15 L). The resulting aqueous layer wasback-extracted with DCM (1.5 L X 2) and the combined DCM layers werewashed with brine. Upon concentration, 150 g of compound C6 wasobtained.

The acidic water layer from the original filtration was made alkalinewith saturated aqueous Na₂CO3 solution (5 L) and extracted with DCM (1 LX 2). The DCM layer was dried over Na₂SO₄, filtered, and concentrated togive 30 g of compound C6. The batches of compound C6 were combined toprovide the title compound C6. Yield: 430 g (80%). ¹H NMR (400 MHz,CDCl₃): δ 8.85 (br. s., 1H), 8.05-8.18 (m, 2H), 7.71 (d, 1H), 7.12 (s,1H), 4.08 (s, 3H).

Step 5. Synthesis of 1-chloro-7-methoxyisoquinoline-6-carbonitrile (P1)

To a suspension of compound C6 (700 g, 3.5 moles) in DCM (14 L) wasadded phosphoryl chloride (333.5 mL, 3.5 moles) dropwise over a periodof about 1 h. After the addition was completed, the reaction mixture wasa homogeneous solution and was stirred at about 25° C. overnight. Aftercompletion of the reaction, the mixture was poured into ice water (5 L)and the resulting solid was filtered. The solid was washed withsaturated aqueous NaHCO₃ solution (1 L×2), followed by water. Upondrying, 360 g of compound P1 with 93% HPLC purity was obtained.

The DCM layer resulting from the filtration was separated. The aqueouslayer resulting from the filtration was extracted with DCM (1 L X 2).The combined DCM solutions were washed with saturated aqueous NaHCO₃solution, followed sequentially by water and brine. The DCM solution wasdried over Na₂SO₄, filtered, and concentrated to provide 300 g ofcompound P1 with 75% HPLC purity. This material was taken in a mixtureof AcOH (900 mL) and EtOAc (1200 mL) mixture, then heated to about70-75° C. for about 30 min. The solid was filtered while the mixture wasstill hot (about 70° C.). The solid was further washed with EtOAc (300mL), followed by hexane (350 mL) and dried to afford 200 g of compoundP1 with 95% HPLC purity.

The P1 with 93% HPLC purity (360 g, 93%) was further purified bytituration with a mixture of EtOAc and MTBE (1:1, v/v) and filtered.Upon drying, 300 g of compound P1 was recovered. The batches of P1 werecombined to provide the title compound P1. Yield: 500 g (65%). ¹H NMR(400 MHz, CDCl₃): δ 8.30 (d, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.58 (d,1H), 7.15 (s, 3H).

Preparation 2: 1-chloro-7-isopropoxyisoquinoline-6-carbonitrile (P2)

Step 1. Synthesis of 3-bromo-4-isopropoxybenzaldehyde (CAS 191602-84-3,C7)

A mixture of 3-bromo-4-hydroxybenzaldehyde (1500 g, 7.5 mol) and K₂CO3(1290 g, 9.3 mol) in anhydrous DMSO (15 L) was treated with2-bromopropane (1010 g, 8.2 mol) and stirred at about 55° C. forovernight. An additional 200 g (1.6 mol) of 2-bromopropane was added andthe reaction was continued for approximately an additional 4 h. Thereaction was cooled to about 30° C. and EtOAc (22.5 L) and water (22.5L) were added. The EtOAc phase was separated and the aqueous phase wasback—extracted with EtOAc (2×7.5 L). The combined EtOAc phases werewashed with water (2×15 L) followed by brine (15 L), dried over Na₂SO₄,filtered, and concentrated to provide the title compound C7. Yield: 1800g (99%). ¹H NMR (400 MHz, CDCl₃) δ 9.82 (s, 1H), 8.07-8.08 (d, 1H),7.76-7.79 (d, 1H), 6.98 (d, 1H), 4.67-4.74 (m, 1H), 1.42-1.44 (d, 6H).

Step 2. Synthesis of (E)-3-(3-bromo-4-isopropoxyphenyl)acrylic acid (CAS1344851-82-6, C8)

Compound C7 (1800 g, 7.4 mol) in anhydrous pyridine (7.56 L) was treatedwith malonic acid (1002 g, 9.6 mmol) and piperidine (316 g, 3.7 mmol)and heated to reflux for about 2 h. The solvent was removed bydistillation under reduced pressure. This was treated with cold water(37.8 L) and stirred for about 0.5 h, then acidified to adjust pH toabout 4.0 with AcOH (about 300 mL). The suspension was vigorouslystirred for about 1 hour to break up all solids and then the product wascollected by filtration, washed with water (3.6 L) and dried undervacuum to provide the title compound C8. Yield: 2014 g (95%). ¹H NMR(400 MHz, dmso-d₆) δ 7.94-7.95 (d, 1H) 7.64-7.67 (dd, 1H), 7.48-7.52 (d,1H), 7.14-7.16 (d, 1H), 6.43-6.47 (d, 1H), 4.71-4.77 (m, 1H), 1.29-1.31(d, 6H).

Step 3. Synthesis of (E)-3-(3-bromo-4-isopropoxyphenyl)acryloyl azide(C9)

To a stirred solution of compound C8 (1000 g, 3.5 mol) in acetone (17.5L), Et₃N (355 g, 3.5 mol) was added and the mixture was cooled to about−5° C. Ethyl chloroformate (495 g, 4.56 mol) was added dropwise,maintaining the temperature at about −5° C. After completion of theaddition, the mixture was stirred for approximately an additional 1 h atabout −5° C. A solution of sodium azide (342 g, 5.3 mol) in water (1264mL) was added slowly at about −5° C. After the addition of sodium azidesolution was complete, the reaction mixture was slowly warmed to about25° C. and stirred for about 0.5 h. The reaction mass was quenched byaddition to water (50 L) and stirring for about 30 minutes at about 25°C. The precipitate was filtered, washed with water (2 L) and dried toprovide the title compound C9. Yield: 978 g (90%). ¹H NMR (300 MHz,dmso-d₆) δ 8.07-8.08 (d, 1H), 7.74-7.77 (dd, 1H), 7.60 (s, 1H),7.16-7.20 (d, 1H), 6.60-6.66 (d, 1H), 4.74-4.82 (m, 1H), 1.29-1.32 (d,6H).

Step 4. Synthesis of 6-bromo-7-isopropoxyisoquinolin-1(2H)-one (C10)

To a mixture of diphenyl ether (8 L) and tri n-butyl amine (328 g, 1.77mol) pre-heated to about 230° C., compound C9 (550 g, 1.77 mol)dissolved in diphenyl ether (2.5 L) was added while the temperature wasmaintained at about 230° C. After the addition was completed, stirringand heating were continued for about 0.5 h. The reaction mixture wascooled to about 25° C. and added slowly to hexane (27.5 L). Theresulting slurry was cooled to about 0° C. and stirred for about 0.5 h.The crude precipitate was filtered the precipitate was washed with coldhexane (5.5 L). The wet cake was dried under vacuum to afford 310 g ofcrude C10.

This reaction was repeated three more times to afford 1064 g of crudeC10. This was dissolved in THF (5.3 L) at reflux and cooled to about 0°C. The slurry was stirred for about 0.5 h and then filtered and thefilter cake was dried under vacuum to afford 574 g of C10. The filtratewas concentrated and purified by chromatography to afford an additional181 g to provide the title compound C10. Yield: 755 g (46%). ¹H NMR (300MHz, CDCl₃) δ 8.24-8.26 (d, 1H), 8.16 (s, 1H), 7.65 (s, 1H), 7.55-7.56(d, 1H), 4.85-4.91 (m, 1H), 1.51-1.52 (d, 6H).

Step 5. Synthesis of7-isopropoxy-1-oxo-1,2-dihydroisoquinoline-6-carbonitrile (C11)

Compound C10 (490 g, 1.74 mol) and zinc cyanide (265 g, 2.25 mol) wereadded to dry DMF (9.8 L) and stirred well for about 5 min at 25° C. Thereaction mixture was degassed with nitrogen for about 20 minutes, afterwhich tetra(kis)triphenylphosphinepalladium (0) (120 g, 0.104 mol) wasadded and the reaction mixture was stirred for about 5 min at about 25°C. before being heated to about 100° C. The mixture was maintained forabout 16 hours at about 100° C. The reaction mixture was cooled to about25° C., diluted with EtOAc (4.9 L), and stirred for about 0.5 h. Themixture was filtered through celite, which was washed with EtOAc (1 L).The combined filtrate was concentrated at pressure of about 10 torr atabout 75° C. Water (4.9 L) was added to the residue and the mixture wasstirred for about 0.5 h. The precipitate was filtered, washed with water(1 L) and dried under vacuum at about 60° C. The precipitate was stirredfor about 0.5 h with MTBE (4.9 L) and filtered. This process wasrepeated twice more, after which the filter cake was washed with MTBE(0.5 L) and dried under vacuum at about 60° C. to provide the titlecompound C11. Yield: 390 g (98%)¹H NMR (400 MHz, CDCl₃) δ 8.24-8.26 (d,1H), 8.16 (s, 1H), 7.65 (s, 1H), 7.54-7.56 (d, 1H), 4.85-4.99 (m, 1H),1.51-1.52 (d, 6H).

Step 6. Synthesis of 1-chloro-7-isopropoxyisoquinoline-6-carbonitrile(P2)

Compound C11 (390 g, 1.7 mol) and POCl₃ (10.97 kg, 71.5 mol) werestirred for about 5 min at about 25° C., then heated to about 100° C.and maintained at about 100° C. for about 0.5 h. The reaction mixturewas cooled to about 25° C. and concentrated under reduced pressure atabout 60° C. The residue was quenched with ice (7.8 kg), thenneutralized with 25% K₂CO3 solution (7.8 L) with stirring until themixture was about pH=7. The solution was extracted with DCM (3×5 L), andthe combined extracts were washed with 10% NaHCO₃ solution (2×3.9 L).The DCM was separated, dried over Na₂SO₄, filtered, and concentrated.n-Heptane (3.9 L) was added to the residue and the mixture was stirredfor about 0.5 h at about 25° C. The precipitate was filtered and thefilter cake was washed with n-heptane (390 mL) and dried under vacuum atabout 60° C. to provide the title compound P2. Yield: 338 g (80%)¹H NMR(300 MHz, dmso-d₆) δ 8.73 (s, 1H), 8.29-8.31 (d, 1H), 7.89-7.91 (d, 1H),7.67 (s, 1H), 5.02-5.06 (m, 1H), 1.41-1.43 (d, 6H).

Preparation 3: 4-chloro-6-methoxyquinazoline-7-carbonitrile (P3) Step 1.Synthesis of 3-hydroxy-4-iodobenzoic acid (CAS 58123-77-6, C12)

To a stirred solution of 3-hydroxybenzoic acid (25 g, 181 mmol) in water(180 mL) were added 1 M aqueous NaOH (188 mL) and sodium iodide (28.1 g,188 mmol), followed by slow addition aqueous sodium hypochloritesolution (0.9 M, 209 mL). The mixture was stirred at about 25° C. forabout 2 h, then cooled in ice and acidified with concentrated HCl topH=3. A sufficient quantity of 10% ascorbic acid solution was added toafford a colorless mixture. The remaining precipitate was filtered,washed with water, and dissolved in EtOAc. The EtOAc solution was washedwith brine, dried over Na₂SO₄, filtered and concentrated to provide thetitle compound C12. Yield: 34 g (71%)¹H NMR (400 MHz, dmso-d₆) δ 12.98(br s, 1H), 10.65 (s, 1H), 7.78 (dd, 1H), 7.32 (d, 1H), 7.11 (dd, 1H).

Step 2. Synthesis of methyl 4-iodo-3-methoxybenzoate (CAS 35387-92-9,C13)

To a stirred solution of compound C12 (84 g, 318 mmol) in DMF (300 mL)at about 0° C. was added K₂CO3 (177 g, 1273 mmol) followed by methyliodide (79.3 mL, 1273 mmol). The mixture was stirred at about 25° C. forabout 16 h, then diluted with EtOAc (2 L) and washed with water (600mL×2), followed by brine (100 mL×2). The EtOAc was dried over Na₂SO₄,filtered and concentrated to provide the title compound C13. Yield: 84 g(90%)¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, 1H), 7.44 (d, 1H), 7.36 (dd,1H), 3.93 (s, 3H), 3.91 (s, 3H).

Step 3. Synthesis of methyl 4-iodo-5-methoxy-2-nitrobenzoate (C14)

A stirred solution of compound C13 (10 g, 38 mmol) in AcOH (92 mL) wastreated with 70% concentrated HNO₃ (11.9 mL) with cooling in an about25° C. water bath, after which acetic anhydride (46 mL) was added. Themixture then placed in a pre-heated oil bath at about 70° C. After about2 h, the reaction mixture was cooled to about 25° C., diluted with 1 MNaOH solution (200 mL), and extracted with EtOAc (200 mL×2). Thecombined extracts were washed with NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography to provide the title compound C14. Yield: 10 g (78%)¹HNMR (400 MHz, dmso-d₆) δ 8.50 (s, 1H), 7.32 (s, 1H), 4.01 (s, 3H), 3.84(s, 3H).

Step 4. Synthesis of methyl 2-amino-4-iodo-5-methoxybenzoate (C15)

To a stirred solution of compound C14 (19 g, 56 mmol) in MeOH (300 mL)was added a solution of stannous chloride dihydrate (40.7 g, 180 mmol)in 120 mL of 6 M HCl. The mixture was stirred at about 25° C. for about16 h, then concentrated. The residue was stirred with a saturatedaqueous solution of potassium fluoride and extracted twice with EtOAc.The combined extracts were dried over Na₂SO₄, filtered and concentrated.The residue was triturated with a mixture of DCM and hexane to providethe title compound C15. Yield: 14 g (81%)¹H NMR (400 MHz, dmso-d₆) δ7.35 (s, 1H), 7.14 (s, 1H), 3.79 (s, 3H), 3.68 (s, 3H).

Step 5. Synthesis of 7-iodo-6-methoxyquinazolin-4(3H)-one (C16)

A stirred solution of compound C15 (17 g, 55 mmol) in formamide (170 mL)was heated at about 160° C. for about 18 h. The reaction mixture wascooled to about 25° C., diluted with water (170 mL), and stirred atabout 10° C. for about 30 minutes. The precipitate was filtered, washedwith water followed by diethyl ether, and dried under vacuum to providethe title compound C15. Yield: 12 g (71%)¹H NMR (400 MHz, dmso-d₆) δ8.14 (s, 1H), 7.99 (s, 1H), 7.44 (s, 1H), 7.16 (br s, 1H), 3.93 (s, 3H).

Step 6. Synthesis of6-methoxy-4-oxo-3,4-dihydroquinazoline-7-carbonitrile (C17)

A stirred solution of compound C16 (16 g, 53 mmol) in dimethyl acetamide(80 mL) was degassed with argon for about 15 minutes, after which zinccyanide (6.22 g, 53 mmol) was added, followed by TMEDA (2.38 mL, 16mmol), tris(dibenzylideneacetone)dipalladium(0) (4.85 g, 5.3 mmol) andXantphos (3.06 g, 5.3 mmol). The mixture was heated at about 80° C. forabout 5 h under argon, then cooled to about 25° C., diluted with diethylether (1 L), and filtered. The precipitate was dissolved in a mixture ofMeOH and DCM (1/4, v/v) and filtered through Celite®. The filtrate wasconcentrated and the residue was purified by column chromatography toprovide the title compound C17. Yield: 5.4 g (50%)¹H NMR (400 MHz,dmso-d₆) δ 12.47 (br. s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.69 (s, 1H),4.02 (s, 3H).

Step 7. Synthesis of 4-chloro-6-methoxyquinazoline-7-carbonitrile (P3)

A mixture of compound C17 (10 g, 49.8 mmol) and POCl₃ (250 mL) washeated at about 100° C. for about 16 h, then cooled to about 25° C. andconcentrated. The residue was diluted with EtOAc and the ethyla acetatesolution was washed with water, saturated aqueous NaHCO₃ solution,brine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography to provide the title compound P3.Yield: 2.8 g (27%)¹H NMR (400 MHz, dmso-d₆) δ 9.11 (s, 1H), 8.75 (s,1H), 7.66 (s, 1H), 4.14 (s, 3H).

Preparation 4: 4-chloro-6-isopropoxyquinoline-7-carboxamide (P4)

Step 1. Synthesis of methyl 2-hydroxy-5-nitrobenzoate (C18)

Concentrated H₂SO₄ (150 mL) was added slowly to a solution of2-hydroxy-5-nitrobenzoic acid (1000 g, 5.4 mol) in dry MeOH (5 L). Afterthe addition was complete, the mixture was heated to reflux for about 24h. After completion of the reaction, the mixture was filtered and theprecipitate was reserved. The filtrate was concentrated to afford asolid residue. This residue and the previous precipitate were dissolvedin EtOAc and washed with water twice. The EtOAc was then washed withbrine, dried over Na₂SO₄, filtered, and concentrated to provide thetitle compound C18. Yield: 900 g (84%)¹H NMR (300 MHz, CDCl₃) δ 11.42(s, 1H), 8.80-8.79 (d, 1H), 8.31-8.35 (dd, 1H), 7.07-7.10 (d, 1H), 4.04(s, 3H).

Step 2. Synthesis of methyl 2-isopropoxy-5-nitrobenzoate (C19)

Compound C18 (900 g, 4.56 mol), triphenylphosphine (1.33 kg, 5.02 mol)and 2-propanol (3.8 kg, 5.02 mol) were dissolved in dry THF (18 L) andcooled to about 5° C. Di-isopropyl-azodicarboxylate (1.01 kg, 5.02 mol)was added, and the reaction was allowed to warm to about 25° C. and wasstirred overnight. The mixture was concentrated under reduced pressureand the residue treated with EtOAc (5 L). The undissolved solids thatremained were removed by filtration, and the filtrate was evaporated.The residue was purified by column chromatography to provide the titlecompound C19. Yield: 760 g (70%)¹H NMR (300 MHz, CDCl₃) δ 8.60 (d, 1H),8.29-8.34 (dd, 1H), 7.01 (d, 1H), 4.73-4.77 (m, 1H), 3.90 (s, 3H), 1.33(d, 6H).

Step 3. Synthesis of methyl 5-amino-2-isopropoxybenzoate (C20)

A solution of compound C19 (760 g, 3.17 mol) in EtOH (12 L) was treatedwith palladium on carbon (76 g) and this mixture was stirred for about 1h at about 25° C. under an atmosphere of hydrogen at about 50 psig.After completion of the reaction, the mixture was filtered throughcelite and filter cake was washed with additional EtOH. The filtrate wasevaporated to provide the title compound C20. Yield: 600 g (60%). ¹H NMR(400 MHz, dmso-d₆) δ 6.83-6.85 (d, 1H), 6.76-6.79 (dd, 1H), 4.31-4.37(m, 1H), 3.86 (s, 3H), 2.80-3.60 (br. s, 2H), 1.29-1.31 (d, 6H).

Step 4. Synthesis of methyl5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-isopropoxybenzoate(C21)

A mixture of compound C20 (600 g, 2.88 mol), Meldrum's acid (640 g, 3.44mol), and triethyl orthoformate (560 g, 3.44 mol) in EtOH (7 L) washeated at reflux overnight. The mixture was cooled to about 20° C. andthe resulting precipitate was collected by filtration to provide thetitle compound C21. Yield: 620 g (60%)¹H NMR (300 MHz, CDCl₃) δ11.07-11.17 (br. d, 1H), 8.53-8.58 (d, 1H), 7.69-7.70 (d, 1H), 7.29-7.33(dd, 1H), 7.02-7.05 (d, 1H), 4.55-4.62 (m, 1H), 2.91 (s, 3H), 1.75 (d,6H), 1.38-1.40 (d, 6H).

Step 5. Synthesis of methyl6-isopropoxy-4-oxo-1,4-dihydroquinoline-7-carboxylate (C22)

Compound C21 (20 g, 55 mmol) was added in portions to pre-heatedDowtherm A (480 mL) at about 240° C. Heating and stirring at thattemperature were continued for approximately an additional 5 minutesafter completion of the addition. The mixture was cooled to about 20° C.and purified by column chromatography to give 6.2 g of a mixture ofcompound C22 and methyl6-isopropoxy-4-oxo-1,4-dihydroquinoline-5-carboxylate. This procedurewas repeated 29 times more with same scale to provide a mixture of thetitle compound C22 and and methyl6-isopropoxy-4-oxo-1,4-dihydroquinoline-5-carboxylate. Yield: 311 g(72%)¹H NMR (400 MHz, dmso-d₆) δ 11.90 (s, 2H), 7.94-7.92 (d, 1H),7.87-7.86 (d, 1H), 7.83 (s, 1H), 7.62-7.54 (m, 3H), 6.01-6.02 (d, 1H),5.93-5.91 (d, 1H), 4.72-4.66 (m, 1H), 4.62-4.56 (m, 1H), 3.85 (s, 3H),3.76 (s, 3H), 1.29-1.31 (d, 6H), 1.20-1.22 (d, 6H).

Step 6. Synthesis of6-isopropoxy-4-oxo-1,4-dihydroquinoline-7-carboxylic acid (C23)

The mixture of compound C22 and methyl6-isopropoxy-4-oxo-1,4-dihydroquinoline-5-carboxylate (311 g, 1.19 mol)was added to THF (1.55 L) and water (1.55 L). Lithium hydroxidemonohydrate (199 g, 4760 mmol) was added and the mixture was stirred atabout 25° C. overnight. The reaction mixture was diluted with water andextracted with EtOAc 4 times until the methyl6-isopropoxy-4-oxo-1,4-dihydroquinoline-5-carboxylate was absent fromthe aqueous phase. The aqueous layer was adjusted to about pH=1 by theaddition of 1 M HCl and the aqueous layer was extracted with EtOActwice. The combined EtOAc extracts were dried over Na₂SO₄, filtered, andconcentrated to provide the title compound C23. Yield: 129 g (44%)¹H NMR(400 MHz, dmso-d₆) δ 11.6-13.0 (br. s, 1H), 8.04-8.06 (d, 1H), 7.84 (s,1H), 7.60 (s, 1H), 6.20-6.22 (d, 1H), 4.69-4.73 (m, 1H), 1.30-1.32 (d,6H).

Step 7. Synthesis of 4-chloro-6-isopropoxyquinoline-7-carboxamide (P4)

A mixture of compound C23 (129 g, 520 mmol) and POCl₃ (2 L) was heatedunder reflux for about 6 h. The mixture was concentrated under reducedpressure to give a dark oil, which was immediately treated with 10 L ofa saturated solution of ammonia gas in dioxane at about 0° C. Themixture was then stirred at about 25° C. overnight. The reaction mixturewas filtered and the filtrate was concentrated. The residue was dilutedwith DCM (1 L) and washed with water. The DCM extract was concentratedto obtain a solid residue which was purified by trituration with diethylether to provide the title compound P4. Yield: 55 g (40%)¹H NMR (300MHz, dmso-d₆) S 8.90 (s, 1H), 8.71-8.72 (d, 1H), 7.80 (br. s, 1H), 7.50(s, 1H), 4.90 (m, 1H), 1.47 (d, 6H).

Preparation 5: 5-hydroxy-3-methoxy-2-naphthamide (P5) Step 1. Synthesisof methyl 3,5-dihydroxy-2-naphthoate (C24)

A solution of 3,5-dihydroxy-2-naphthoic acid (2.2 kg, 10.8 mol) inanhydrous MeOH (16 L) was cooled to below 25° C., after which thionylchloride (2.56 kg, 21.5 mol) was then added over a period of about 3 h.After the addition, the mixture was stirred at about 25° C. overnight.An additional 500 g of thionyl chloride was added slowly and the mixturewas stirred for approximately another 16 hours until the reaction wascomplete. The reaction mixture was concentrated to dryness and theresidue was taken up in cold water. The resulting suspension wasadjusted to about pH=8 with aqueous NaHCO₃. The precipitate wasfiltered, washed with water (0.5 L x 3) and dried under vacuum toprovide the title compound C24. Yield: 2.25 kg (96%)¹H NMR (400 MHz,dmso-d₆) δ 10.19 (s, 1H), 10.18 (s, 1H), 8.37 (s, 1H), 7.49 (s, 1H),7.39-7.42 (d, 1H), 7.14-7.18 (t, 1H), 6.88-6.90 (d, 1H), 3.95 (s, 3H).

Step 2. Synthesis of methyl5-((tert-butyldiphenylsilyl)oxy)-3-hydroxy-2-naphthoate (C25)

To a solution of compound C24 (500 g, 2.3 mol) in 1,2-dichloroethane(7.5 L) was added imidazole (233 g, 3.4 mol). After the addition, themixture was heated to about 45° C. and stirred for about 45 minutesbefore t-butyldiphenylsilyl chloride (453 g, 2.7 mol) was addeddropwise. The mixture was then heated to about 65° C. and held at thattemperature for about two hours. Water (3 L) was added to the mixtureand the dichloroethane layer was separated. The aqueous phase wasextracted with DCM (1 L x 2). The combined DCM extracts were washed withwater (2 L x 2) and brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. Cold MeOH was added to the residue and stirredfor about 10 minutes. The precipitate was filtered, washed with coldMeOH, and dried under vacuum to provide the title compound C25. Yield:900 g (86%) This process was repeated to prepare additional compoundC25. ¹H NMR (300 MHz, dmso-d₆) δ 10.35 (s, 1H), 8.42 (s, 1H), 7.77 (s,1H), 7.69-7.72 (t, 4H), 7.52 (m, 7H), 6.90-6.96 (t, 1H), 6.37-6.41 (d,1H), 3.97 (s, 3H), 1.13 (s, 9H).

Step 3. Synthesis of methyl5-((tert-butyldiphenylsilyl)oxy)-3-methoxy-2-naphthoate (C26)

Triphenylphosphine (1.15 kg, 4.4 mol) was dissolved in THF (13 L) andtreated with diisopropylazodicarboxylate (885 g, 4.4 mol) with stirringand cooling to maintain the temperature below about 25° C. After theaddition was complete, the mixture was stirred for about 10 minutes.Methanol (876 mL, 21.9 mol) was then added into the mixture over aperiod of about 1 h with cooling to maintain the temperatureapproximately below 25° C. Compound C25 (1.0 kg, 2.2 mol) was added intothe mixture in portions. The resulting solution was heated to about 80°C. for about 1 h. The mixture was then cooled to about 25° C. andconcentrated to dryness. The residue was purified by columnchromatography, after which it was heated under reflux with a 3/1mixture of EtOH and petroleum ether for about 1 h to provide the titlecompound C26. Yield: 500 g (49%) This process was repeated to prepareadditional compound C26. ¹H NMR (300 MHz, dmso-d₆) S 8.24 (s, 1H),7.61-7.77 (m, 5H), 7.42-7.52 (m, 7H), 7.01-7.06 (t, 1H), 6.50-6.53 (d,1H), 3.97 (s, 3H), 3.86 (s, 3H), 1.13 (s, 9H).

Step 4. Synthesis of 5-hydroxy-3-methoxy-2-naphthoic acid (C27)

Compound C26 (1.33 kg, 2.8 mol) and lithium hydroxide monohydrate (475g, 11.3 mol) were added to a mixture of THF (3 L), MeOH (500 mL) andwater (3 L). The mixture was stirred at about 25° C. overnight, afterwhich the mixture was diluted with EtOAc (4 L) and water (2 L). Theaqueous phase was separated and the EtOAc phase was extracted with water(2 L x 2). The combined aqueous phases were extracted with EtOAc (2 L x2) and then acidified to about pH=3 with concentrated HCl. Theprecipitate was filtered, washed with water (1 L x 3), and dried invacuum to provide the title compound C27. Yield: 533 g (86%).

This process was repeated to prepare additional compound C27. ¹H NMR(400 MHz, dmso-d₆) δ 12.80 (br. s, 1H), 10.16 (s, 1H), 8.12 (s, 1H),7.50 (s, 1H), 7.37 (d, 1H), 7.15-7.24 (m, 1H), 6.92 (dd, 1H), 3.90 (s,3H).

Step 5. Synthesis of 5-hydroxy-3-methoxy-2-naphthamide (P5)

A suspension of compound C27 (80 g, 360 mmol) in a mixture of DMF (15mL) and dry THF (2 L) was treated with oxalyl chloride (64 mL) at about25° C. The resulting suspension was stirred for about 1 h, then it wasconcentrated to dryness and the residue was suspended in 2 L of dry THFand cooled in ice. Concentrated ammonium hydroxide (220 mL) was addedover a period of about five to ten minutes. The resulting mixture wasthen stirred at about 25° C. for approximately another twenty minutes.Saturated aqueous NaHCO₃ (100 mL) was added and the THF was evaporatedunder reduced pressure. Water (1 L) was added and the precipitate wasfiltered, washed with water, and dried under vacuum. The resulting solidwas suspended in EtOAc and heated under reflux for about 2 h. The solidwas filtered, washed with EtOAc, and dried to provide the title compoundP5. Yield: 51 g (65%) By repetition of these steps a total of 1.0 kg ofP5 was prepared. ¹H NMR (400 MHz, dmso-d₆) δ 10.19 (s, 1H), 8.21 (s,1H), 7.80-7.81 (br. s, 1H), 7.60-7.61 (br. s, 1H), 7.51 (s, 1H),7.38-7.41 (d, 2H), 7.19-7.20 (t, 1H), 6.97-6.99 (d, 1H), 3.96 (s, 3H).

Synthesis of 5-hydroxy-3-isopropoxy-2-naphthamide (P6)

This compound was prepared in the same manner as compound P5,substituting 2-propanol for MeOH in the reaction of compound C25 in Step3, to provide the title compound P6. ¹H NMR (400 MHz, dmso-d₆) δ9.00-10.8 (br. s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.55(s, 1H), 7.35-7.37 (d, 1H), 7.16-7.20 (t, 1H), 6.90-6.91 (d, 1H),4.80-4.86 (m, 1H), 1.39-1.41 (d, 1H).

Preparation 6: 1-chloro-7-ethoxyisoquinoline-6-carbonitrile (P7)

Step 1. Synthesis of 1-chloro-7-hydroxyisoquinoline-6-carbonitrile (C28)

To a stirred solution of compound P2 (10.0 g, 40.6 mmol) in 250 mL ofDCM was added anhydrous aluminum chloride (16.3 g, 122 mmol). Thereaction mixture was heated under reflux for about 4 h. The supernatantliquid was removed by decantation and ice was added to the residueremaining in the flask, which was broken up manually to afford a lightyellow suspension. This solid was filtered and washed with water, dried,and was washed with ether to provide the title compound C28. Yield: 8.1g (97%)¹H NMR (400 MHz, dmso-d₆) δ 11.95 (s, 1H), 8.65 (s, 1H), 8.22 (d,1H), 7.84 (d, 1H), 7.69 (s, 1H).

Step 2. Synthesis of 1-chloro-7-ethoxyisoquinoline-6-carbonitrile (P7)

To a stirred solution of compound C28 (9.0 g, 44.1 mmol) in 190 mL ofDMF was added potassium t-butoxide (6.9 g, 61.8 mmol) at 0° C. Afterabout 15 minutes, iodoethane (8.8 mL, 110 mmol) was added. The reactionmixture was allowed to warm to about 25° C. and was stirred for about 4h. The reaction mixture was diluted with water and the resultingprecipitate was filtered and dried. The precipitate was then trituratedwith a mixture of MeOH and diethyl ether (9/1, v/v) to provide the titlecompound P7. Yield: 7.6 g (83%)¹H NMR (400 MHz, dmso-d₆) δ 8.72 (s, 1H),8.31 (d, 1H), 7.90 (d, 1H), 7.62 (s, 1H), 7.62 (s, 1H), 4.37 (q, 2H),1.47 (t, 3H).

Synthesis of 1-chloro-7-(prop-2-yn-1-yloxy)isoquinoline-6-carbonitrile(P8)

This compound was prepared in the same manner as compound P7,substituting 3-bromoprop-1-yne for iodoethane in the reaction ofcompound C28 in Step 2, to provide the title compound P8. ¹H NMR (400MHz, dmso-d₆) δ 8.78 (s, 1H), 8.34 (d, 1H), 7.93 (d, 1H), 7.84 (s, 1H),5.25 (s, 2H), 3.79 (s, 1H).

Synthesis of 1-chloro-7-methoxy-d₃-isoquinoline-6-carbonitrile (P9)

This compound was prepared in the same manner as compound P7,substituting methyl-d₃ 4-methylbenzenesulfonate for iodoethane in thereaction of compound C28 in Step 2, to provide the title compound P9. ¹HNMR (400 MHz, dmso-d₆): S 8.73 (s, 1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.63(s, 1H).

Synthesis of 1-chloro-7-(2-methoxyethoxy)isoquinoline-6-carbonitrile(P10)

This compound was prepared in the same manner as compound P7,substituting 1-bromo-2-methoxyethane for iodoethane in the reaction ofcompound C28 in Step 2, to provide the title compound P10. ¹H NMR (400MHz, CDCl₃) δ 8.28 (d, 1H), 8.16 (s, 1H), 7.70 (s, 1H), 7.56 (d, 1H),4.40 (t, 2H), 3.90 (t, 2H), 3.51 (s, 3H).

Preparation 7;1-chloro-7-(cyclopropylmethoxy)isoquinoline-6-carbonitrile (P11)

Step 1. Synthesis of1-chloro-7-(cyclopropylmethoxy)isoquinoline-6-carbonitrile (P11)

A solution of triphenylphosphine (0.78 g, 3.0 mmol) in THF (8 mL) wastreated with diisopropylazodicarboxylate (0.61 g, 3 mmol). After about 5minutes, cyclopropylmethanol (0.29 g, 4.0 mmol) was added, followed bycompound C28 (0.41 g, 2.0 mmol). The mixture was heated for about 1.5 h,then cooled and concentrated. The residue was triturated with MeOH andfiltered to provide the title compound P11. ¹H NMR (400 MHz, dmso-d₆) δ8.75 (s, 1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.64 (s, 1H), 4.20 (d, 1H),1.35 (m, 1H), 0.65 (d, 2H), 0.46 (d, 2H).

Synthesis of 1-chloro-7-tert-butoxyisoquinoline-6-carbonitrile (P12)

This compound was prepared in the same manner as compound P11,substituting 2-methyl-2-ropanol for cyclopropylmethanol in the reactionof compound C28 in Step 1, to provide the title compound P12. ¹H NMR(400 MHz, CDCl₃) δ 8.29 (d, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.58 (d,1H), 1.63 (s, 9H)

Synthesis of 1-chloro-7-cyclobutoxyisoquinoline-6-carbonitrile (P13)

This compound was prepared in the same manner as compound P11,substituting cyclobutanol for cyclopropylmethanol in the reaction ofcompound C28 in Step 1, to provide the title compound P13. ¹H NMR (400MHz, dmso-d₆) δ 8.75 (s, 1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.50 (s, 1H),5.10 (quin, 1H), 2.60-2.56 (m, 2H), 2.26-2.18 (m, 2H), 1.93-1.83 (m,1H), 1.83-1.73 (m, 1H).

Synthesis of 1-chloro-7-(oxetan-3-yloxy)isoquinoline-6-carbonitrile(P14)

This compound was prepared in the same manner as compound P11,substituting oxetan-3-ol for cyclopropylmethanol in the reaction ofcompound C28 in Step 1, to provide the title compound P14. ¹H NMR (400MHz, dmso-d₆) δ 8.81 (s, 1H), 8.35 (d, 1H), 7.94 (d, 1H), 7.27 (s, 1H),5.63-5.81 (m, 1H), 5.06 (t, 1H), 4.69 (m, 2H).

Preparation 8: 4-chloro-6-isopropoxyquinoline-7-carbonitrile (P15)

Step 1. Synthesis of 4-chloro-6-isopropoxyquinoline-7-carbonitrile (P15)

Phosphorus oxychloride (28.2 mL, 303 mmol) was added drop wise withstirring to a solution of compound P4 (20 g, 75.8 mmol), pyridine (91mL, 1.13 mol) and imidazole (10.3 g, 151.5 mmol) in DCM (300 mL). Themixture was stirred at about 25° C. for about 30 minutes. The reactionmixture was then cooled in ice and quenched with cold water (100 mL),added slowly enough to maintain the temperature to approximately below5° C. Stirring was continued for approximately another 20 minutes withcooling. The mixture was then poured into 1 M HCl (500 mL) andseparated. The aqueous phase was extracted with DCM. The combined DCMextracts were washed with 1 M HCl, water, Na₂CO3 solution, brine, driedover Na₂SO₄, filtered and concentrated to provide the title compoundP15. Yield: 12 g (64%)¹H NMR: (400 MHz, CDCl₃) δ 8.70 (d, 1H), 8.41 (s,1H), 7.54 (d, 1H), 7.52 (s, 1H), 4.85 (quin, 1H), 1.50 (d, 6H).

Preparation 9: 4-chloro-6-methoxyquinoline-7-carbonitrile (P16) Step 1.Synthesis of 4-chloro-6-hydroxyquinoline-7-carbonitrile (C29)

To a stirred solution of compound P15 (12.0 g, 48.6 mmol) in 180 mL ofDCM was added anhydrous aluminum chloride (20.6 g, 155 mmol). Thereaction mixture was heated under reflux overnight. The solvent wasevaporated under reduced pressure, and the residue was stirred with 0.1M HCl (400 mL) at 25° C. for 2 h. The remaining solid was filtered,washed with water, MeOH, and dried to provide the title compound C29.Yield: 9.6 g (96%)¹H NMR: (400 MHz, dmso-d₆) δ 11.82 (s, 1H), 8.74 (d,1H); 8.56 (s, 1H), 7.81 (d, 1H), 7.60 (s, 1H).

Step 2. Synthesis of 4-chloro-6-methoxyquinoline-7-carbonitrile (P16)

To a stirred solution of compound C29 (9.6 g, 46.9 mmol) in DMF (190 mL)was added potassium t-butoxide (6.8 g, 61 mmol) at 0° C. After about 15minutes, iodomethane (7.3 mL, 117 mmol) was added. The reaction mixturewas allowed to warm to about 25° C. and was stirred for about 2 h. Thereaction mixture was diluted with water and the resulting precipitatewas filtered and dried. This solid was washed with water, hexane, anddried under vacuum to provide the title compound P15. Yield: 8.1 g(79%)¹H NMR: (400 MHz, CDCl₃) δ 8.73 (d, 1H), 8.41 (s, 1H), 7.56 (d,1H); 7.52 (s, 1H), 4.09 (s, 3H).

Synthesis of 4-chloro-6-ethoxyquinoline-7-carbonitrile (P17)

This compound was prepared in the same manner as compound P16,substituting iodoethane for iodomethane in the reaction of compound C30in Step 3, to provide the title compound P17. ¹H NMR: (400 MHz, dmso-d₆)δ 8.72 (s, 1H), 8.31 (d, 1H), 7.89 (d, 1H), 7.62 (s, 1H), 4.38 (q, 2H),1.46 (t, 3H).

Preparation 10: 1-chloro-7-(difluoromethoxy)isoquinoline-6-carbonitrile(P18)

Step 1. Synthesis of1-chloro-7-(difluoromethoxy)isoquinoline-6-carbonitrile (P18)

A solution of compound C27 (164 mg, 0.8 mmol) in DMF (2 mL) was treatedwith sodium difluoroacetate (95 mg, 0.8 mmol) and cesium carbonate (285mg, 0.9 mmol). The mixture was heated at about 60° C. for about 1 h. Themixture was diluted with 25 mL of water and 25 mL of EtOAc, and theEtOAc was separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography toprovide the title compound P18. Yield 133 mg (65%). ¹H NMR: (400 MHz,dmso-d₆) δ 8.93 (s, 1H), 8.48 (d, 1H), 8.07 (d, 1H), 8.02 (dd, 1H), 7.70(t, 1H).

Preparation 11: 6-bromo-1-chloro-7-(trifluoromethoxy)isoquinoline (P19)

Step 1. Synthesis of 6-bromo-1-chloro-7-(trifluoromethoxy)isoquinoline(P19)

A suspension of 6-bromo-7-(trifluoromethoxy)isoquinolin-1(2H)-one (CAS1445564-99-7, 410 mg, 1.3 mmol) in 6 mL of POCl₃ was heated under refluxfor about 40 minutes. The mixture was cooled in ice and then poured intoice water with vigorous stirring. After the ice had melted, the mixturewas extracted with EtOAc (100 mL). The EtOAc was separated and stirredwith saturated aqueous NaHCO₃ solution (100 mL) until no bubblingoccurred. The EtOAc was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silicachromatography to provide the title compound P19. Yield 130 mg (31%)¹HNMR (400 MHz, CDCl₃) δ 8.36 (d, 1H), 8.24 (d, 1H), 8.22 (s, 1H), 7.56(d, 1H).

Preparation 12: 1-Chloro-7-cyclopropoxyisoquinoline-6-carbonitrile (P21)

Step 1. Synthesis of1-chloro-7-(2-chloroethoxy)isoquinoline-6-carbonitrile (C166)

A mixture of compound C28 (2.4 g, 11.8 mmol),2-chloroethanol-1-(4-methylbenzenesulfonate) (CAS 80-41-1, 5.5 g, 23.5mmol), Triton-405 (6.63 g, 11.8 mmol) and cesium carbonate (4.58 g, 14.1mmol) in 96 mL of THF was heated for about 8 h at about 65° C. Themixture was diluted with water and extracted with EtOAc. The combinedEtOAc extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC166. Yield: 2.0 g (64%). LCMS: MH⁺=267.0.

Step 2. Synthesis of 1-chloro-7-(vinyloxy)isoquinoline-6-carbonitrile(C167)

A solution of compound C166 (1.4 g, 5.3 mmol) in THF (50 mL) was treatedwith a solution of potassium t-butoxide (1.2 g, 10.6 mmol) in 15 mL ofTHF at about −20° C., after which the mixture was warmed to about 25° C.and stirred for about 1 h Saturated aqueous NH₄Cl was added and themixture was extracted with EtOAc. The combined EtOAc extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC167. Yield: 1.1 g (90%). LCMS: MH⁺=230.9.

Step 3. Synthesis of 1-Chloro-7-cyclopropoxyisoquinoline-6-carbonitrile(P21)

A solution of compound C167 (220 mg, 0.9 mmol) in 50 mL of DCM wastreated sequentially at about 0° C. with ethereal diazomethane (150 mL),followed by palladium(II) acetate (25 mg). The mixture was stirredovernight at about 25° C., then the mixture was filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound P21. Yield: 30 mg (13%). ¹H NMR (400 MHz, dmso-d₆) δ8.22-8.21 (d, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.51-7.50 (d, 1H),3.99-3.95 (m, 1H), 0.97-0.88 (m, 4H).

Preparation 13: 3,4-dichloro-6-methoxyquinoline-7-carbonitrile (P22)

Step 1. Synthesis of 3-chloro-7-iodo-6-methoxyquinolin-4(1H)-one (C168)

A solution of 7-iodo-6-methoxyquinolin-4(1H)-one (CAS 1300031-68-8, 2.0g, 6.6 mmol) and N-chlorosuccinimide (976 mg, 7.3 mmol) in AcOH (20 mL)was heated at about 35° C. for about 18 h. It was filtered and theprecipitate was dried to provide the title compound C168. Yield: 1.4 g(63%). ¹H NMR (400 MHz, dmso-d₆) δ 12.25 (br. s, 1H), 8.35 (s, 1H), 8.11(s, 1H), 7.47 (s, 1H), 3.91 (s, 3H).

Step 2. Synthesis of 3,4-dichloro-6-methoxyquinoline-7-carbonitrile(P22)

A mixture of compound C168 (2.6 g, 7.7 mmol) and cuprous cyanide (1.31g, 15.5 mmol) in pyridine (26 mL) was heated at about 120° C. for about16 h. The mixture was cooled to about 25° C., filtered, and the filtratewas concentrated. The residue was suspended in toluene and concentrated,then treated with POCl₃ (15 mL, 160 mmol) and triethylaminehydrochloride (1.47 g, 10.7 mmol). The mixture was heated at reflux forabout 3 h, then cooled to about 25° C. and concentrated. The residue wasstirred with aqueous NaHCO₃. The resulting precipitate was filtered,washed with n-hexane, and dried under vacuum. The dry solid wassuspended in a 9/1ratio of MeOH/DCM and solid NaHCO₃ was added. Thismixture was stirred for about 5 h, filtered and the filtrate wasconcentrated. The residue was triturated with diethyl ether and driedunder vacuum to provide the title compound P22. Yield: 1.5 g (56%). ¹HNMR (400 MHz, dmso-d₆) δ 8.98 (s, 1H), 8.71 (s, 1H), 7.60 (s, 1H), 4.11(s, 3H).

Preparation 14: 4-bromo-1-chloro-7-isopropoxyisoquinoline-6-carbonitrile(P23)

Step 1. Synthesis of7-isopropoxy-1-oxo-1,2-dihydroisoquinoline-6-carbonitrile (C169)

A solution of compound P2 (10.0 g, 40 mmol) and hydrogen chloride in1,4-dioxane (4 M, 100 mL) in water (100 mL) was heated in a sealed tubeat about 120° C. for about 18 h. The mixture was cooled to about 25° C.and diluted with water. The precipitate was filtered, washed with water,and dried to provide the title compound C169. Yield: 7.5 g (81%). ¹H NMR(300 MHz, dmso-d₆) δ 11.5 (br. s, 1H), 8.21 (s, 1H), 7.77 (s, 1H),7.12-7.16 (t, 1H), 6.53-6.56 (d, 1H), 4.85-4.93 (m, 1H), 1.35-1.37 (d,6H).

Step 2. Synthesis of4-bromo-7-isopropoxy-1-oxo-1,2-dihydroisoquinoline-6-carbonitrile (C170)

A solution of N-bromosuccinimide (14 g, 78 mmol) in acetonitrile (150mL) was added drop wise to a suspension of compound C169 (15 g, 65 mmol)in acetonitrile (1.38 L) at about 25° C. and stirred for about 24 h toafford a yellow suspension. The reaction mixture was concentrated tohalf volume. The precipitate was filtered, washed with diethyl ether anddried to provide the title compound C170. Yield: 13.0 g (65%). ¹H NMR(400 MHz, dmso-d₆) δ 11.8 (br. s, 1H), 8.08 (s, 1H), 7.84 (s, 1H),7.52-7.53 (d, 1H), 4.92-4.98 (m, 1H), 1.36-1.38 (d, 6H).

Step 3. Synthesis of4-bromo-1-chloro-7-isopropoxyisoquinoline-6-carbonitrile (P23)

A suspension of compound C170 (10.0 g, 32 mmol) in POCl₃ (120 mL) washeated at reflux for about 1.5 h. The mixture was concentrated and theresidue was dissolved in DCM. The DCM extract was washed with K2CO3,brine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography to provide the title compound P23. Yield: 9 g(85%). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.42 (s, 1H), 7.65 (s,1H), 4.87-4.93 (m, 1H), 1.52-1.53 (d, 6H).

Preparation 15: 4-hydroxy-6-methoxyisoquinoline-7-carbonitrile (P24)

Step 1. Synthesis of ethyl 2-((3-bromo-4-methoxybenzyl)amino)acetate(C173)

To a solution of glycine ethyl ester hydrochloride (17 g, 126 mmol) andEt₃N (25.2 g, 252 mmol) in DCM (100 mL) and MeOH (100 mL) was addedsodium triacetoxyborohydride (53.1 g, 252 mmol) at about 0° C. Themixture was stirred for about 30 min before3-bromo-4-methoxybenzaldehyde (26.8 g, 126 mmol) was added, then themixture allowed to warm up to about 25° C. for about 18 h. Water (200mL) and saturated aqueous NH₄Cl (100 mL) were added and the mixture wasextracted with DCM. The combined DCM extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography to provide the title compound C173. Yield: 15 g (45%).¹H NMR (400 MHz, dmso-d₆) δ 7.52 (d, 1H), 7.26 (dd, 1H), 7.05 (d, 1H),4.08 (q, 2H), 3.82 (s, 3H), 3.64 (s, 2H), 3.27 (s, 2H), 2.67 (br. s.,1H), 1.19 (t, 3H).

Step 2. Synthesis of ethyl2-(N-(3-bromo-4-methoxybenzyl)-4-methylphenylsulfonamido)acetate (C174)

To a solution of compound C173 (18 g, 60 mmol) and pyridine (24 g, 298mmol) in THF (400 mL) was added tosyl chloride (11.4 g, 60 mmol) at 0°C. The mixture was stirred for about 16 h at about 25° C., thenacidified to about pH 3 with concentrated HCl and extracted with DCM(3×300 mL). The combined DCM extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C174. Yield: 17 g (63%). ¹HNMR (400 MHz, CDCl₃) δ 7.68 (d, 2H), 7.26 (d, 2H), 7.19 (s, 1H), 7.11(dd, 1H), 6.76 (d, 1H), 4.33 (s, 2H), 3.94 (q, 2H), 3.83 (s, 2H), 3.81(s, 3H), 2.37 (s, 3H), 1.08 (t, 3H).

Step 3. Synthesis of2-(N-(3-bromo-4-methoxybenzyl)-4-methylphenylsulfonamido)acetic acid(C175)

To a solution of compound C174 (17 g, 37 mmol) in THF (100 mL) and MeOH(100 mL) was added a solution of lithium hydroxide (1.7 g, 74 mmol) inwater (100 mL) at about 25° C. The mixture was stirred for about 4 h,then the mixture was partially concentrated to remove THF and MeOH. Theremaining solution was acidified to about pH 3 with concentrated HCl andextracted with DCM (3×100 mL). The combined DCM extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated to provide thetitle compound C175. Yield: 15 g (94%). ¹H NMR (400 MHz, CDCl₃) δ 7.75(d, 2H), 7.33 (d, 2H), 7.27 (s, 1H), 7.17 (d, 1H), 6.83 (d, 1H), 4.38(s, 2H), 3.93 (s, 2H), 3.88 (s, 3H), 2.43 (s, 3H).

Step 4. Synthesis of7-bromo-6-methoxy-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one (C176)

To a solution of compound C1175 (4.27 g, 10 mmol) in DCM (120 mL) wereadded 2 drops of DMF followed by oxalyl chloride (6.3 g, 50 mmol) atabout 25° C. After about 2 h, the mixture was evaporated. The residuewas dissolved in DCM (100 mL) and cooled to about −78° C. Anhydrousaluminum chloride (3.32 g, 25 mmol) was added in portions. The mixturewas stirred for about 40 min at about −78° C., then stirred for about 2h at about 0° C. Water was added, and the DCM was separated washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue wastriturated with a mixture of MeOH (7.5 mL) and EtOAc (7.5 mL). Theprecipitate was collected by filtration and dried to provide the titlecompound C176. Yield: 1.9 g (46%). ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d,2H), 7.47 (s, 1H), 7.31 (s, 1H), 7.27 (d, 2H), 4.43 (s, 2H), 3.99 (s,2H), 3.89 (s, 3H), 2.39 (s, 3H).

Step 5. Synthesis of 7-bromo-6-methoxyisoquinolin-4-ol (C177)

A mixture of compound C176 (1.9 g, 4.6 mmol) and NaHCO₃ (1.54 g, 18.5mmol) in EtOH (50 mL) was heated at reflux for about 2 h, then cooled toabout 25° C. and concentrated. The residue was treated with EtOAc andwater. The EtOAc was separated and the aqueous phase was extracted withadditional EtOAc. The combined EtOAc extracts were dried over Na₂SO₄,filtered and concentrated. The residue was purified by chromatography toprovide the title compound C177. Yield: 300 mg (26%). ¹H NMR (400 MHz,dmso-d₆) δ 10.50 (br. s., 1H), 8.67 (s, 1H), 8.39 (s, 1H), 8.03 (s, 1H),7.47 (s, 1H), 4.01 (s, 3H).

Step 6. Synthesis of 4-hydroxy-6-methoxyisoquinoline-7-carbonitrile(P24)

A mixture of compound C177 (100 mg, 0.39 mmol), zinc cyanide (231 mg, 2mmol) and tetrakis(triphenylphosphine)palladium (0) (45 mg, 0.04 mmol)in 5 mL of DMF was stirred for about 10 min at about 25° C., then heatedat about 140° C. for about 6 h. The mixture was cooled, concentrated,the residue was treated with water, and extracted with EtOAc. The EtOAcextract was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound P24. Yield: 65 mg (82%).

¹H NMR (400 MHz, dmso-d₆) δ 10.74 (s, 1H), 8.78 (s, 1H), 8.71 (s, 1H),8.13 (s, 1H), 7.53 (s, 1H), 4.06 (s, 3H).

Preparation 16: 8-fluoro-5-hydroxy-3-methoxy-2-naphthamide (P25) Step 1.Synthesis of methyl 5-hydroxy-3-methoxy-2-naphthoate (C178)

A solution of compound C26 (40 g, 85 mmol) in THF (150 mL) was treatedwith tetra-n-butylammonium fluoride (31 g, 119 mmol) and stirred for 30min at 25° C. The reaction mixture was neutralized with AcOH beforebeing diluted with water and EtOAc. The EtOAc extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C178. Yield: 16.50 g (89%).¹H NMR (400 MHz, dmso-d₆) δ 10.19 (s, 1H), 8.21 (s, 1H), 7.53 (s, 1H),7.39-7.42 (d, 1H), 7.19-7.22 (t, 1H), 6.96 (d, 1H), 3.92 (s, 3H), 3.85(s, 3H).

Step 2. Synthesis of methyl 8-fluoro-5-hydroxy-3-methoxy-2-naphthoate(C179)

A solution of SelectFluor (3.18 g, 8.6 mmol) in DMF (10 mL) was addedslowly to a solution of compound C178 (2.00 g, 8.6 mmol) in DMF (20 mL)at about 0° C. After stirring overnight, the mixture was diluted withbrine and extracted with EtOAc. The combined EtOAc extracts were driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C179. Yield: 90 mg (4%). ¹HNMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 7.52 (d, 1H), 6.86 (dd, 1H), 6.77(dd, 1H), 3.98 (s, 3H), 4.02 (s, 3H). ¹⁹F NMR (400 MHz, CDCl₃) δ−130.68.

Step 3. Synthesis of 8-fluoro-5-hydroxy-3-methoxy-2-naphthamide (P25)

A solution of compound C179 (90 mg, 0.36 mmol) in THF (4 mL) and water(2.5 mL) was treated with lithium hydroxide (88 mg, 3.6 mmol) at about20° C. After stirring overnight, the mixture was acidified with 1 M HCland concentrated to dryness. The residue was stirred in DCM (5 mL) andtreated with oxalyl chloride solution (2 M, 0.27 mL) along with acatalytic amount of DMF. After about 1 h at about 20° C., the mixturewas filtered and concentrated to dryness. The residue was taken up inTHF (2 mL) and treated with ammonia in dioxane solution (0.5 M, 1 mL) atabout 20° C. After about 1 h, the mixture was filtered and concentrated.The residue was purified by chromatography to provide the title compoundP25. Yield 27 mg (32%). ¹H NMR (400 MHz, dmso-d₆) δ 10.17 (br. s., 1H),8.32 (s, 1H), 7.81 (br. s., 1H), 7.66 (br. s., 1H), 7.53 (s, 1H), 7.00(dd, 1H), 6.82 (dd, 1H), 3.98 (s, 3H). ¹⁹F NMR (400 MHz, dmso-d₆) δ−134.39.

Preparation 17:(S)-3,3-dimethyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one (P20)

Step 1. Synthesis of(S)-3,3-dimethyl-5-(trimethylsilyloxy)-1,3,7,7α-tetrahydropyrrolo[1,2-c]oxazole(C30)

A solution of diisopropylamine (147 mL, 1.05 mol) in dry THF (875 mL)was cooled to about −25° C. and treated with n-butyllithium (2.5 M inhexanes, 387 mL, 970 mmol). The mixture was stirred at about −20° C. forabout 30 minutes, then cooled to about −70° C. A solution of(S)-3,3-dimethyltetraz-hydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS99208-71-6, 125 g, 806 mmol) in THF (163 mL) was added, maintaining thetemperature approximately below −60° C. After the addition wascompleted, the mixture was stirred for approximately an additional 5minutes before the addition of TMSCl (132 mL, 1.05 mol) at −60° C. Themixture was then allowed to warm to about −10° C. before beingconcentrated under reduced pressure. The residue was stirred with dryhexanes (1 L) and concentrated, then again stirred with dry hexanes (1L) and concentrated. The residue was stirred with dry hexanes (1 L),filtered, and concentrated under reduced pressure to provide the titlecompound C30 which was carried on to Step 2 without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 4.16 (m, 1H), 4.00 (dd, 1H),3.75 (dd, 1H), 3.56 (dd, 1H), 2.54 (m, 1H), 2.31 (dd, 1H), 1.49 (s, 3H),1.36 (s, 3H), 0.24 (s, 9H).

Step 2. Synthesis of(S)-3,3-dimethyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one (P20)

The crude compound C30 from Step 1 was dissolved in THF (915 mL) andtreated with allyl methyl carbonate (104 mL, 911 mmol) and palladium(II)acetate (9.0 g, 40 mmol). The mixture was heated to about 65 C until gasevolution ceased, and was then heated for approximately an additional 1h after gas evolution ceased. The mixture was then cooled to about 25°C. and concentrated under reduced pressure. The residue was purified bycolumn chromatography to provide the title compound P20. Yield: 90 g(73%)¹H NMR (400 MHz, CDCl₃) δ 7.07 (dd, 1H) 6.09 (dd, 1H) 4.60-4.71 (m,1H) 4.13 (dd, 1H) 3.33 (dd, 1H) 1.67 (s, 3H) 1.56 (s, 3H).

Preparation 18: (5S)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one (L1)

Step 1. Synthesis of(7aS)-3,3,6-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (C31)

To a solution of(S)-3,3-dimethyltetra-hydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS99208-71-6, 3.0 g, 19 mmol) in 50 mL of THF was added LDA (2 M, 12.1 mL,20 mmol) at about −78° C. The reaction mixture was stirred for about 30minutes, then iodomethane (3.03 g, 21 mmol) was added. The reactionmixture was maintained for about 10 minutes at about −78° C., thenallowed to warm to about 25° C. for about 1 h. The reaction was quenchedby addition to EtOAc (10 mL) and water (10 mL). The EtOAc was separatedand the aqueous phase was extracted with additional EtOAc (50 mL×2). Thecombined EtOAc extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated to provide the title compound C31. Yield 3.1 g(92%). ¹H NMR (400 MHz, CDCl₃) δ 4.11 (m, 2H), 3.42 (m, 1H), 2.87 (dt,1H), 2.38 (m, 1H), 1.65 (s, 3H), 1.46 (s, 3H), 1.36 (m, 2H), 1.20 (s,1.5H), 1.19 (s, 1.5H).

Step 2 Synthesis of (5S)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one (L1)

A solution of compound C31 (58 mg, 0.34 mmol) in MeOH (1.1 mL) wastreated with 4-toluenesulfonic acid (1.4 mg, 7 μmol). The resultingmixture was stirred at 60° C. for about 4 h, The mixture wasconcentrated under vacuum to provide the title compound L1. Yield 38 mg(86%)¹H NMR (400 MHz, CDCl₃) δ 3.70-3.83 (m, 2H), 3.39-3.49 (m, 1H),2.51-2.64 (m, 1H), 2.30-2.42 (m, 1H), 1.34-1.46 (m, 1H), 1.23 (s, 1.5H),1.21 (s, 1.5H).

Synthesis of (5S)-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L2)

This compound was prepared in the same manner as compound L1,substituting NFSI for iodomethane in Step 1. ¹H NMR (400 MHz, CD₃OD) δ5.24-5.11 (m, 1H), 3.83-3.32 (m, 3H), 2.68-1.88 (m, 2H).

Synthesis of (3R,5R)-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L3)

This compound was prepared in the same manner as compound L1,substituting (R)-3,3-dimethyltetra-hydropyrrolo[1,2-c]oxazol-5(1H)-one(CAS 103630-36-0, Chemical Communications, 2011, 47, 10037-10039) for(S)-3,3-dimethyltetra-hydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS99208-71-6), and NFSI for iodomethane, in Step 1, followed by separationof the diastereomeric products. ¹H NMR (400 MHz, CDCl₃) δ 4.96-5.16 (m,1H), 3.64-3.72 (m, 2H), 3.41-3.49 (m, 1H), 2.53-2.63 (m, 1H), 1.85-2.02(m, 1H).

Synthesis of (5S)-3-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (L4)

This compound was prepared in the same manner as compound L1,substituting bromoethane for iodomethane in Step 1. ¹H NMR (400 MHz,CDCl₃) δ 4.03-4.17 (m, 2H), 3.37-3.47 (m, 1H), 2.69-2.83 (m, 1H),2.51-2.65 (m, 1H), 2.37 (s, 1H), 1.86-1.96 (m, 1H), 1.33-1.44 (m, 1H),1.02 (t, 1H), 0.95 (t, 3H).

Synthesis of (5S)-5-(hydroxymethyl)-3-(methoxymethyl)pyrrolidin-2-one(L5)

This compound was prepared in the same manner as compound L1,substituting chloro(methoxy)methane for iodomethane in Step 1. ¹H NMR(400 MHz, CDCl₃) δ 3.63-3.84 (m, 2H), 3.46-3.63 (m, 2H), 3.38 (s, 3H),2.64-2.75 (m, 1H), 2.17-2.39 (m, 2H), 1.75-2.05 (m, 1H).

Synthesis of(3R,5S)-5-(hydroxymethyl)-3-(2-hydroxypropan-2-yl)pyrrolidin-2-one (L11)

This compound was prepared in the same manner as compound L1,substituting acetone for iodomethane in Step 1. ¹H NMR (400 MHz, CDCl₃)δ 6.27-6.42 (m, 1H), 3.62-3.77 (m, 2H), 3.50-3.59 (m, 1H), 2.59-2.72 (m,1H), 1.92-2.04 (m, 2H), 1.23 (s, 6H).

Synthesis of(5S)-3-((benzyloxy)methyl)-5-(hydroxymethyl)pyrrolidin-2-one (L12)

This compound was prepared in the same manner as compound L1,substituting CAS 3587-60-8 (“benzyloxymethyl chloride”) for iodomethanein Step 1. ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.41 (m, 5H), 6.58 (br. s.,1H), 4.46-4.63 (m, 2H), 3.61-3.85 (m, 4H), 3.41-3.53 (m, 1H), 2.66-2.80(m, 1H), 2.30 (m, 1H), 1.98 (s, 1H).

Synthesis of (3S,5S)-3-hydroxy-5-(hydroxymethyl)pyrrolidin-2-one (L13)

This compound was prepared in the same manner as compound L1,substituting CAS 104372-31-8 for iodomethane in Step 1. ¹H NMR (400 MHz,dmso-d₆) δ 4.41 (dd, 1H), 4.07 (dd, 1H), 3.82-3.93 (m, 1H), 3.34-3.42(m, 1H), 2.41-2.49 (m, 1H), 1.45-1.53 (m, 1H).

Synthesis of (3R,5S)-3-hydroxy-5-(hydroxymethyl)pyrrolidin-2-one (L14)

This compound was prepared in the same manner as compound L1,substituting CAS 127184-05-8 for iodomethane in Step 1. ¹H NMR (400 MHz,dmso-d₆) δ 5.79 (d, 1H), 4.22-4.32 (m, 1H), 4.16 (td, 1H), 4.01 (dd,1H), 3.32-3.36 (m, 1H), 3.17 (d, 1H), 1.84-1.95 (m, 2H).

Synthesis of(3S,5S)-5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)pyrrolidin-2-one (L15)and (3R,5S)-5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)pyrrolidin-2-one(L16)

These compounds were prepared in the same manner as compound L1,substituting 1,1,1-trifluoro-2-iodoethane, added slowly, for iodomethanein Step 1, followed by separation of the diastereomeric products bysilica gel chromatography prior to Step 2. Application of Step 2 to theindividual diastereomers provided the title compounds L15 and L16. L15:¹H NMR (400 MHz, CDCl₃) δ 6.48 (br. s., 1H), 3.67-3.79 (m, 2H),3.52-3.62 (m, 1H), 2.74-2.91 (m, 2H), 2.28 (dd, 1H), 1.99-2.15 (m, 2H).L16: ¹H NMR (400 MHz, CDCl₃) δ 6.12 (br. s., 1H) 3.77-3.86 (m, 2H)3.43-3.52 (m, 1H) 2.83-2.98 (m, 1H) 2.71-2.82 (m, 1H) 2.45-2.56 (m, 1H)1.99-2.15 (m, 1H) 1.89 (dd, 1H) 1.51-1.58 (m, 1H).

Synthesis of(5S)-5-(hydroxymethyl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrrolidin-2-one(L20)

This compound was prepared in the same manner as compound L1,substituting tetrahydro-4H-pyran-4-one (CAS 29943-42-8) for iodomethanein Step 1. 1H NMR (400 MHz, CDC₃N) δ 4.30 (d, 1H), 3.60-3.77 (m, 4H),3.51-3.60 (m, 1H), 3.43-3.51 (m, 1H), 3.34-3.42 (m, 1H), 2.93 (t, 1H),2.51 (t, 1H), 1.98-2.08 (m, 1H), 1.86-1.94 (m, 2H), 1.80 (ddd, 1H),1.58-1.69 (m, 1H), 1.41-1.52 (m, 1H), 1.24 (dd, 1H).

Synthesis of(5S)-5-(hydroxymethyl)-3-(3-hydroxyoxetan-3-yl)pyrrolidin-2-one (L22)

This compound was prepared in the same manner as compound L1,substituting CAS 6704-31-0 (oxetane-3-one) for iodomethane in Step 1 toprovide(6S,7aS)-6-(3-hydroxyoxetan-3-yl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C81), which was used in Step 2. ¹H NMR (400 MHz, dmso-d₆) δ 5.82 (d,1H), 4.70-4.80 (m, 2H), 4.46 (d, 1H), 4.36-4.44 (m, 2H), 3.42 (dd, 1H),3.27-3.31 (m, 1H), 2.80-2.91 (m, 1H), 1.83-1.98 (m, 2H).

Synthesis of (5S)-3-benzyl-5-(hydroxymethyl)pyrrolidin-2-one (L28)

This compound was prepared in the same manner as compound L1,substituting benzyl bromide for iodomethane in Step 1. ¹H NMR (400 MHz,dmso-d₆) δ 7.64 (s, 1H), 7.31 (t, 2H), 7.24 (m, 3H), 4.74 (t, 1H),3.16(q, 2H), 3.02 (dd, 1H), 2.64 (m, 2H), 2.54 (s, 1H), 1.82 (m, 2H).

Synthesis of(3R,5S)-3-fluoro-5-(hydroxymethyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-one(L31)

This compound was prepared in the same manner as compound L1,substituting compound C49 for compound C30 and NFSI for iodomethane inStep 1. ¹H NMR (400 MHz, CDCl₃) δ 4.03 (dd, 1H), 3.98 (d, 1H), 3.73 (d,1H), 3.66-3.64 (m, 1H), 3.58-3.55 (m, 1H), 3.47-3.38 (m, 2H), 2.51-2.40(m, 1H), 2.32-2.26 (m, 2H), 1.91 (ddd, 1H), 1.80 (d, 1H), 1.56-1.36 (m,2H).

Preparation 19:(3S,5S)-3-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L7)

Step 1. Synthesis of(7aS)-6-ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (C32)

To a solution of(S)-3,3-dimethyltetra-hydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS99208-71-6, 1.0 g, 6.4 mmol) in 30 mL of THF was added LDA (2 M, 4.0 mL,8.0 mmol) at about −78° C. The reaction mixture was stirred for about 30minutes, then bromoethane (0.80 g, 7.2 mmol) was added. The reactionmixture was maintained for about 10 minutes at about −78° C., thenallowed to warm to about 25° C. for about 25 minutes. The reaction wasquenched by addition to EtOAc (10 mL) and water (10 mL). The EtOAc wasseparated and the aqueous phase was extracted with additional EtOAc (50mL×2). The combined EtOAc extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated to provide the title compound C32.Yield 0.80 g (68%)¹H NMR (400 MHz, CDCl₃) δ 4.04-4.18 (m, 2H), 3.35-3.49(m, 1H), 2.71-2.84 (m, 1H), 2.50-2.65 (m, 1H), 2.13-2.38 (m, 1H),1.77-1.96 (m, 1H), 1.68 (s, 1H), 1.64 (s, 2H), 1.47 (s, 3H), 1.35-1.44(m, 1H), 1.02 (t, 1H), 0.94 (t, 2H).

Step 2. Synthesis of(6S,7aS)-6-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C33) and(6R,7aS)-6-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C34)

To a solution of compound C32 (0.80 g, 4.4 mmol) in 5 mL of THF wasadded LDA (2 M, 2.8 mL, 5.6 mmol) at about −78° C. The reaction mixturewas stirred for about 30 minutes, then treated with a solution ofN-fluorobis(benzenesulfonyl)imide (NFSI) (1.65 g, 5.3 mmol) in 10 mL ofTHF. The reaction mixture was maintained for about 10 minutes at about−78° C., then allowed to warm to about 25° C. for about 1 h. Thereaction was quenched by addition to EtOAc (10 mL) and water (10 mL).The EtOAc was separated and the aqueous phase was extracted withadditional EtOAc (50 mL×2). The combined EtOAc extracts were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in DCM (20 mL) and filtered. The filtrate was concentrated andthe residue was separated by column chromatography to provide the titlecompounds C33 (Yield: 180 mg, 20%) and C34 (Yield: 403 mg, 45%).

C33: ¹H NMR (400 MHz, CDCl₃) δ 4.17 (dd, 1H), 3.84-3.95 (m, 1H), 3.47(dd, 1H), 2.54 (ddd, 1H), 1.95-2.11 (m, 2H), 1.78-1.95 (m, 1H), 1.72 (s,3H), 1.49 (s, 3H), 1.07 (t, 3H).

C34: ¹H NMR (400 MHz, CDCl₃) δ 4.29-4.40 (m, 1H), 4.17 (dd, 1H),3.34-3.43 (m, 1H), 2.42 (ddd, 1H), 1.98-2.11 (m, 1H), 1.76-1.83 (m, 1H),1.71 (ddd, 1H), 1.65 (s, 3H), 1.53 (s, 3H), 1.01 (t, 3H).

Step 3; Synthesis of(3S,5S)-3-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L7)

A solution of compound C33 (180 mg, 0.9 mmol) in MeOH (5 mL) was treatedwith 4-toluenesulfonic acid (23 mg, 135 μmol). The resulting mixture wasstirred at about 70° C. for about 4 h, The mixture was concentratedunder vacuum to provide the title compound L7. Yield 150 mg (100%). ¹HNMR (400 MHz, CDCl₃) δ 3.75 (dd, 1H), 3.69 (dd, 1H), 3.56 (dd, 1H),2.31-2.44 (m, 1H), 1.96-2.12 (m, 2H), 1.68-1.85 (m, 1H), 1.03 (t, 3H).

Synthesis of (S)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (L6)

This compound was prepared in the same manner as compound L7,substituting NFSI for bromoethane in Step 1. ¹H NMR (400 MHz, CDCl₃) δ4.07-4.18 (m, 1H), 3.78-3.92 (m, 1H), 2.72-2.83 (m, 1H), 2.04-2.18 (m,1H).

Synthesis of (3R,5S)-3-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L8)

This compound was prepared in the same manner as compound L7,substituting compound C34 for compound C33 in Step 3. ¹H NMR (400 MHz,CDCl₃) δ 3.90-4.01 (m, 1H), 3.81 (dd, 1H), 3.46 (dd, 1H), 2.29-2.47 (m,1H), 2.00-2.11 (m, 1H), 1.83-2.00 (m, 1H), 1.64-1.83 (m, 1H), 1.02 (t,3H).

Synthesis of (3R,5S)-3-fluoro-5-(hydroxymethyl)-3-methylpyrrolidin-2-one(L9) and (3S,5S)-3-fluoro-5-(hydroxymethyl)-3-methylpyrrolidin-2-one(L10)

These compounds were prepared in the same manner as compounds L7 and L8,substituting iodomethane for bromoethane in Step 1, followed byseparation of the diastereomeric products by chromatography prior toStep 2. L9: ¹H NMR (400 MHz, CDCl₃) δ 3.77-3.83 (m, 1H), 3.69-3.77 (m,1H), 3.53-3.62 (m, 1H), 2.42-2.60 (m, 2H), 1.53-1.64 (m, 3H).

L10: ¹H NMR (400 MHz, CDCl₃) δ 3.73-3.80 (m, 1H), 3.70 (td, 1H),3.55-3.63 (m, 1H), 2.26-2.40 (m, 1H), 2.07-2.22 (m, 1H), 1.59 (d, 3H).

Synthesis of(3S,5S)-3-((benzyloxy)methyl)-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L17) and(3R,5S)-3-((benzyloxy)methyl)-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L18)

These compounds were prepared in the same manner as compounds L7 and L8,substituting NFSI for bromoethane in Step 1 and benzyloxymethyl chloride(CAS 3587-60-8) for NFSI in Step 2, followed by separation of thediastereomeric products by chromatography. The individual diastereomerswere then subjected to Step 3. L17: ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.42(m, 5H), 6.40-6.55 (m, 1H), 4.60 (s, 2H), 3.88-4.00 (m, 1H), 3.69-3.85(m, 3H), 3.46 (dd, 1H), 2.35-2.56 (m, 1H), 2.16-2.33 (m, 1H). L18: ¹HNMR (400 MHz, CDCl₃) δ 7.70 (br. s., 1H), 7.24-7.39 (m, 5H), 4.52-4.63(m, 2H), 3.63-3.86 (m, 4H), 3.48 (br. s., 1H), 2.61 (d, 1H), 1.95-2.13(m, 1H).

Synthesis of(3R,5S)-3-fluoro-5-(hydroxymethyl)-3-(2-hydroxypropan-2-yl)pyrrolidin-2-one(L19)

This compound was prepared in the same manner as compound L7,substituting NFSI for bromoethane in Step 1 and acetone for NFSI in Step2, ¹H NMR (400 MHz, CDCl₃) δ 3.45-3.42 (m, 1H), 3.27 (s, 1H), 2.57-2.49(m, 1H), 1.98-1.90 (m, 1H), 1.86-1.83 (m, 3H), 1.32-1.31 (m, 3H).

Synthesis of(5S)-3-hydroxy-5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)pyrrolidin-2-one(L21)

This compound was prepared in the same manner as compound L7,substituting 1,1,1-trifluoro-2-iodoethane, added slowly, for bromoethanein Step 1 and CAS 104372-31-8 for NFSI in Step 2. LCMS: Rt=1.128 min(213.7, MH⁺); 1.258 (213.7, MH⁺).

Synthesis of(5S)-3-fluoro-5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)pyrrolidin-2-one(L26)

This compound was prepared in the same manner as compound L7,substituting(3R,7aS)-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(CAS 170885-05-9) for(S)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS99208-71-6) and 1,1,1-trifluoro-2-iodoethane, added slowly, forbromoethane in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 3.57-3.53 (m, 1H),3.46-3.38 (m, 2H), 2.93-2.80 (m, 1H), 2.70-2.35 (m, 2H), 2.27-2.10 (m,1H).

Preparation 20:(3S,5S)-3-fluoro-3-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L23)

Step 1. Synthesis of (7aS)-methyl3,3-dimethyl-5-oxohexahydropyrrolo[1,2-c]oxazole-6-carboxylate (C35)

To a solution of(S)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (CAS99208-71-6, 7.0 g, 45 mmol) in THF (70 mL) was added LDA (2.0 M, 56.4mL, 113 mmol) dropwise at about −78° C. The reaction mixture was stirredfor about 30 min before being treated with dimethyl carbonate (10.2 g,113 mmol) in one portion. The mixture was stirred for approximatelyanother 10 min at about −78° C. and was then warmed to about 25° C. andstirred for about 1 h. Saturated aqueous potassium dihydrogen phosphatewas added and the mixture was extracted with EtOAc. The extracts weredried over Na₂SO₄ filtered and concentrated. The residue was purified bychromatography to provide the title compound C35. Yield: 6.8 g (71%). ¹HNMR (400 MHz, CDCl₃) δ 4.43-4.53 (m, 1H, minor diastereomer), 4.16-4.25(m, 1H, major diastereomer), 4.08-4.16 (m, 1H, both diastereomers), 3.85(dd, 1H, major diastereomer), 3.81 (s, 3H, major diastereomer), 3.79 (s,3H, minor diastereomer), 3.64 (d, 1H, minor diastereomer), 3.53-3.60 (m,1H, major diastereomer), 3.43-3.51 (m, 1H, minor diastereomer),2.49-2.57 (m, 1H, minor diastereomer), 2.34-2.44 (m, 1H, majordiastereomer), 2.22-2.33 (m, 1H, major diastereomer), 1.98 (dt, 1 Hmminor diastereomer), 1.68 (s, 3H, minor diastereomer), 1.67 (s, 3H,major diastereomer), 1.48 (s, 3H, both diastereomers).

Step 2. Synthesis of (7aS)-methyl6-fluoro-3,3-dimethyl-5-oxohexahydropyrrolo[1,2-c]oxazole-6-carboxylate(C36)

A solution of compound C35 (6.8 g, 32 mmol) in THF (128 mL) was treatedwith DBU (5.8 g, 38 mmol). The mixture was stirred for about 15 min atabout 25° C., then cooled to about 0° C. and treated with NFSI (12.1 g,38 mmol). It was kept at about 0° C. for about 15 min, then warmed toabout 25° C. for about 3 h. The mixture was concentrated, and theresidue was diluted with EtOAc and washed with 10% aqueous K₂CO₃. Themixture was separated and the aqueous layer was extracted with EtOAc.The combined extracts were dried over Na₂SO₄ filtered and concentrated.The residue was purified by chromatography to provide the title compoundC36. Yield: 5.0 g (68%). ¹H NMR (400 MHz, CDCl₃) δ 4.37-4.33 (m, 1H),4.13-4.10 (m, 1H), 3.83 (s, 3H), 3.51-3.43 (m, 1H), 2.49-2.42 (m, 2H),1.61 (s, 3H), 1.46 (s, 3H).

Step 3. Synthesis of(6R,7aS)-6-fluoro-6-(hydroxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C37) and(6S,7aS)-6-fluoro-6-(hydroxymethyl)-3,3-dimethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C38)

A solution of compound C36 (6.0 g, 26 mmol) in EtOH (100 mL) at about 0°C. was treated with NaBH₄ (1.7 g, 44 mmol) added in one portion. Themixture was stirred at about 0° C. for about 1.5 h before being treatedwith 1 M HCl and then concentrated. The residue was purified bychromatography to provide the title compounds C37 (Yield: 1.8 g, 34%)and C38 (Yield: 400 mg, 8%). C37: ¹H NMR (400 MHz, CDCl₃) δ 4.19 (dd,1H), 3.80-4.06 (m, 3H), 3.46-3.54 (m, 1H), 2.79 (ddd, 1H), 2.10 (dd,1H), 1.97-2.08 (m, 1H), 1.72 (s, 3H), 1.50 (s, 3H). C38: ¹H NMR (400MHz, CDCl₃) δ 4.36-4.45 (m, 1H), 4.19 (dd, 1H), 3.93-4.04 (m, 1H),3.78-3.88 (m, 1H), 3.39-3.49 (m, 1H), 2.49 (dd, 1H), 2.40 (ddd, 1H),1.97-2.14 (m, 1H), 1.67 (s, 3H), 1.54 (s, 3H).

Step 4. Synthesis of(6S,7aS)-6-fluoro-6-(fluoromethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C39)

A solution of compound C37 (1.5 g, 7.4 mmol) in CHCl₃ (30 mL) andpyridine (3.0 mL, 37 mmol) was cooled to about −78° C. and treated withDAST (2.1 mL, 16 mmol). The mixture was allowed to warm to about 25° C.and stirred for about 18 h, and then was heated at about 45° C. forabout 2 h. The mixture was cooled to about −78° C. and quenched by theaddition of MeOH. The mixture was allowed to warm to about 25° C.,stirred for about 30 min and concentrated. The residue was purified bychromatography to provide the title compound C39. Yield: 450 mg (30%).¹H NMR (400 MHz, CDCl₃) δ 4.68-4.62 (m, 1H), 4.58-4.51 (m, 1H); 4.19(dd, 1H), 4.03-3.95 (m, 1H), 3.49 (t, 1H), 2.84-2.79 (m, 1H), 2.14-2.03(m, 1H), 1.70 (s, 3H), 1.52 (s, 3H).

Step 5. Synthesis of(3S,5S)-3-fluoro-3-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L23)

To a stirred solution of compound C39 (450 mg, 2.2 mmol) in 50.4 mL ofacetonitrile and 5.6 mL of water was added 4-toluenesulfonic acid (19mg, 0.11 mmol). The reaction mixture was stirred at about 25° C. forabout 16 h and then heated at about 90° C. for about 2 h. The reactionmixture was cooled to about 25° C., concentrated, and the residue waspurified by chromatography to provide the title compound L23. Yield: 260mg (72%). ¹H NMR (400 MHz, CDCl₃) δ 6.47 (br s, 1H), 4.73-4.65 (m, 1H),4.62-4.51 (m, 1H), 3.80-3.74 (m, 1H), 3.58 (br s, 1H), 2.72-2.62 (m,1H), 2.16-2.07 (m, 1H), 2.03-2.00 (m, 1H).

Synthesis of(3R,5S)-3-fluoro-3-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L24)

This compound was prepared in the same manner as compound L23,substituting C38 for C37 in step 4. ¹H NMR (400 MHz, CD₃OD) δ 4.67 (dd,1H), 4.63 (d, 1H), 3.82-3.90 (m, 1H), 3.62 (dd, 1H), 3.48 (dd, 1H),2.27-2.52 (m, 2H).

Preparation 21: (5S)-5-(hydroxymethyl)-3-methoxypyrrolidin-2-one (L25)

Step 1. Synthesis of(3R,7aS)-6-hydroxy-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C40)

To a solution of(3R,7aS)-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(CAS 170885-05-9, 1.0 g, 4.3 mmol) in THF (20 mL) was added LDA (2.0 M,3.0 mL) at about −78° C. The mixture was stirred at about −78° C. forabout 0.5 h, then a solution of (1R)-(−)-10-camphorsulfonyl)oxaziridine(CAS 104372-31-8, 1.0 g, 4.7 mmol) in THF (10 mL) was added dropwise atabout −78° C. The mixture was stirred at about −78° C. for about 10 minand then at about 25° C. for about 1.5 h. 10 mL of EtOAc and 10 mL ofwater were added the mixture was concentrated. The residue was dilutedwith water and extracted with EtOAc. The EtOAc extracts were washed withbrine, dried over MgSO₄ filtered and concentrated. The residue waspurified by chromatography to provide the title compound C40. Yield: 450mg (42%). LCMS: m/z, 250.1 (M+1), retention time: 0.748 min

Step 2. Synthesis of(3R,7aS)-6-methoxy-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C41)

A mixture of compound C40 (468 mg, 1.8 mmol), silver (I) oxide (232 mg,1.0 mmol) and iodomethane (710 mg, 5.0 mmol) in acetonitrile (20 mL) wasstirred about 25° C. for about 6 h. Additional silver (I) oxide (464 mg,2.0 mmol) and iodomethane (710 mg, 5.0 mmol) were added and after about18 h, the mixture was filtered and concentrated to provide the titlecompound C41 which was used without further purification. Yield: 370 mg(75%). LCMS: m/z, 263.9 (M+1), retention time: 0.883 min Step 3.Synthesis of (5S)-5-(hydroxymethyl)-3-methoxypyrrolidin-2-one (L25). Asolution of compound C41 (430 mg, 1.6 mmol) in AcOH (8 mL) and water (2mL) was stirred at about 75° C. for about 30 min. The mixture wasconcentrated, MeOH was added, and the resulting mixture was againconcentrated. The residue was purified by chromatography to provide thetitle compound L25. Yield: 204 mg (86%). ¹H NMR (400 MHz, CD₃OD) δ 6.19(br. s, 1H) 3.89-3.86 (m, 1H), 3.68-3.65 (m, 2H), 3.49-3.43 (m, 4H),2.45-2.42 (m, 1H), 2.30-2.00 (m, 1H), 1.68-1.64 (m, 1H).

Preparation 22: (S)-6-(hydroxymethyl)-5-azaspiro[2.4]heptan-4-one (L27)

Step 1. Synthesis of(S)-3′,3′-dimethyldihydro-1′H-spiro[cyclopropane-1,6′-pyrrolo[1,2-c]oxazol]-5′(3′H)-one(C42)

A solution of (S)-3,3-dimethyltetra-hydropyrrolo[1,2-c]oxazol-5(1H)-one(CAS 99208-71-6, 233 mg, 1.5 mmol) in THF (10 mL) was treated with LDA(2.0 M, 1.6 mL) at about −78° C. A solution of 1,3,2-dioxathiolane2,2-dioxide (CAS 1072-53-3, 242 mg, 1.9 mmol) in THF (10 mL) was addedat a rate to maintain the internal temp at about less than −65° C. Themixture was stirred at about −78° C. for about 10 min then warmed toabout −20° C. The mixture was stirred for about 45 min and graduallywarmed to about −3° C. before being re-cooled to about −78° C. LDA (2.0M, 1.95 mmol) was added and the mixture was stirred for about 10 min atabout −78° C., then slowly warmed to about 25° C. and kept for about 8h. The mixture was treated with half-saturated aqueous NH₄Cl andextracted with EtOAc. The EtOAc extracts were washed with saturatedaqueous NH₄Cl, dried over MgSO₄ filtered and concentrated. The residuewas purified by chromatography to provide the title compound C42. Yield:120 mg (44%). ¹H NMR (400 MHz, CDCl₃) δ 4.29-4.21 (m, 1H), 4.08-4.05 (m,1H), 3.43-3.38 (m, 1H), 2.04-1.99 (m, 1H), 1.94-1.90 (m, 1H), 1.61 (s,3H), 1.45 (s, 3H), 1.19-1.14 (m, 1H), 1.25-1.17 (m, 1H), 1.16-1.14 (m,1H), 0.95-0.94 (m, 1H), 0.93-0.90 (m, 1H).

Step 2. Synthesis of (S)-6-(hydroxymethyl)-5-azaspiro[2.4]heptan-4-one(L27)

To a stirred solution of compound C42 (120 mg, 0.66 mmol) in 4.5 mL ofacetonitrile and 0.5 mL of water was added 4-toluenesulfonic acid (12mg, 0.06 mmol). The reaction mixture was heated at about 90° C. forabout 1 h. The reaction mixture was cooled to about 25° C. andconcentrated to provide the title compound L27 which was used in thenext step without further purification. Yield: 105 mg. ¹H NMR (400 MHz,CD₃OD) δ 3.82-3.82 (m, 1H), 3.80-3.50 (m, 1H), 2.33-2.30 (m, 1H),1.98-1.94 (m, 1H), 1.04-1.02 (m, 2H), 0.81-0.80 (m, 2H).

Preparation 23(3R,5S)-3-fluoro-3-(2-fluoroethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L29)

Step 1. Synthesis of(7aS)-6-allyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (C43)

To a stirred solution of(S)-3,3-dimethyltetra-hydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS99208-71-6, 10 g, 64.5 mmol) in THF (160 mL) at −78° C. was added LDA (2M, 40.3 mL) and the mixture was stirred for about 0.5 h. Allyl bromide(6.2 mL, 71 mmol) was added and mixture was stirred for about 10 min atabout −78° C., then allowed to warm to about 25° C. and stirred forabout 1 h. It was quenched with EtOAc-water (1:1, 60 mL) and separated.The aqueous phase was extracted with EtOAc, and the combined EtOAcextracts dried over Na2SO4 filtered and concentrated. The residue waspurified by chromatography to provide the title compound L29. Yield:8.85 g (70%). ¹H NMR (400 MHz, CDCl₃) δ 5.78-5.71 (m, 1H), 5.14-5.02 (m,2H), 4.13-4.03 (m, 2H), 3.40-3.36 (m, 1H), 2.90-2.72 (m, 1H), 2.63-2.42(m, 1H), 2.35-2.15 (m, 2H), 1.95-1.87 (m, 1H), 1.64 (s, 3H), 1.44 (s,3H).

Step 2. Synthesis of(6S,7aS)-6-allyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C44a)

To a stirred solution of L29 (5.0 g, 25.6 mmol) in THF (80 mL) at −78°C. was added LDA (2 M, 16.0 mL). After about 0.5 h, a solution of NFSI(8.89 g, 28.2 mmol) in THF (20 mL) was added and the mixture was stirredfor about 10 min at about −78° C. The reaction mixture was warmed toabout 25° C. for about 1 h. The mixture was quenched with EtOAc—water(1:1). The aqueous phase was extracted with EtOAc, and the combinedEtOAc extracts were dried over Na₂SO₄ filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC44a. Yield: 1.9 g (35%). There was also obtained the diastereomer C44b.Yield: 1.1 g (20%). C44a: ¹H NMR (400 MHz, CDCl₃) δ 5.78-5.68 (m, 1H),5.19-5.15 (m, 2H), 4.30-4.25 (m, 1H), 4.11 (dd, 1H), 3.33 (t, 1H),2.72-2.65 (m, 1H), 2.55-2.47 (m, 1H), 2.37-2.27 (m, 1H), 1.85-1.70 (m,1H), 1.59 (s, 3H), 1.48 (s, 3H). C44b: ¹H NMR (400 MHz, CDCl₃) δ5.85-5.76 (m, 1H), 5.29-5.23 (m, 2H), 4.14 (dd, 1H), 3.89-3.81 (m, 1H),3.44 (t, 1H), 2.75-2.67 (m, 1H), 2.62-2.51 (m, 2H), 2.06-1.95 (m, 1H),1.54 (s, 3H), 1.47 (s, 3H).

Step 3. Synthesis of(6R,7aS)-6-fluoro-6-(2-hydroxyethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C45)

A stream of ozonized oxygen was bubbled through a solution of compoundC44a (500 mg, 1.4 mmol) in DCM (20 mL) at about −78° C. for about 15min. A stream of argon was passed through the mixture for about 15 min,then the mixture was treated with dimethyl sulfide (5 mL) at about −78°C. and stirred for about 1 h at about −78° C. The reaction mixture wasevaporated to dryness and the residue was dissolved in THF (18 mL) andwater (2 mL). NaBH₄ (183 mg, 4.6 mmol) was added and the mixture wasstirred at about 25° C. for about 2 h. The mixture was treated withsaturated aqueous NH₄Cl solution and extracted with EtOAc. The combinedEtOAc extracts were dried over Na₂SO₄ filtered and concentrated toprovide the title compound C45 as a colorless liquid which was carriedon without further purification. Yield: 370 mg (71%). ¹H NMR (400 MHz,dmso-d₆) δ 4.61 (t, 1H), 4.11-4.08 (m, 1H), 4.00-3.94 (m, 1H), 3.62-3.52(m, 2H), 3.47 (t, 1H), 2.74-2.69 (m, 1H), 2.05-1.91 (m, 3H), 1.56 (s,3H), 1.36 (s, 3H).

Step 4. Synthesis of(6R,7aS)-6-fluoro-6-(2-fluoroethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C46)

To a solution of compound C45 (370 mg, 1.7 mmol) in CHCl₃ (15 mL) wasadded pyridine (0.69 mL, 8.5 mmol) followed by DAST (0.4 mL, 3.07 mmol)at about −78° C. The mixture was warmed to about 25° C. and stirred forabout 18 h. The mixture was then cooled to about −78° C. and quenched bythe slow addition of MeOH. After about 30 min at about −78° C., themixture was warmed to about 25° C. and stirred for about 30 min beforebeing evaporated to dryness. The residue was purified by chromatographyto provide the title compound C46. Yield: 120 mg (32%). ¹H NMR (400 MHz,CDCl₃) δ 4.80-4.53 (m, 2H), 4.17-4.14 (m, 1H), 3.96-3.91 (m, 1H), 3.46(t, 1H), 2.76-2.71 (m, 1H), 2.34-2.19 (m, 2H), 2.09-1.98 (m, 1H), 1.68(s, 3H), 1.44 (s, 3H).

Step 5. Synthesis of(3R,5S)-3-fluoro-3-(2-fluoroethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L29)

To a stirred solution of compound C46 (130 mg, 0.62 mmol) in 5 mL ofacetonitrile and 0.5 mL of water was added 4-toluenesulfonic acid (11mg, 0.06 mmol). The reaction mixture was heated at about 90° C. forabout 1 h. The reaction mixture was cooled to about 25° C.,concentrated, and the residue was purified by chromatography to providethe title compound L29. Yield: 170 mg (83%). ¹H NMR (400 MHz, CDCl₃) δ6.86 (br. s., 1H), 4.52-4.96 (m, 2H), 3.72-3.90 (m, 2H), 3.55-3.72 (m,1H), 2.53-2.73 (m, 1H), 2.31-2.51 (m, 1H), 2.05-2.31 (m, 2H).

Preparation 24:(3R,5S)-5-(hydroxymethyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-one(L30)

Step 1. Synthesis of(6S,7aS)-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-3,3-dimethyltetrahydro-pyrrolo-1,2-c]oxazol-5(3H)-one(C47)

A stirred solution of(S)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (CAS99208-71-6, 10.0 g, 64 mmol) in THF (200 mL) was cooled to about −78° C.and LDA (2 M, 80 mL, 160 mmol) was added. The mixture was stirred atabout −78° C. for about 30 min before tetrahydro-4H-pyran-4-one (CAS29943-42-8, 15 mL, 160 mmol) in THF (50 mL) was added. The mixture wasallowed to warm to about 25° C. and stirred for about 2 h before thereaction was quenched with EtOAc-water (1:1). The EtOAc was separatedand the aqueous layer was extracted with EtOAc. The combined EtOAcextracts were washed with brine, dried over Na₂SO₄ filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C47. Yield: 12 g (74%). ¹H NMR (400 MHz, dmso-d₆) δ 4.14(m, 1H), 3.97-4.07 (m, 3H), 3.34-3.42 (m, 3H), 2.59-2.63 (m, 1H),1.99-2.05 (m, 2H), 1.44-1.67 (m, 10H).

Step 2. Synthesis of(S)-6-(dihydro-2H-pyran-4(3H)-ylidene)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C48)

Triethylamine (38 mL, 274 mmol) was added to a stirred solution ofcompound C47 (7.0 g, 27 mmol) in DCM (150 mL). The resulting mixture wascooled to about 0° C. and methanesulfonyl chloride (10.6 mL, 137 mmol)was added. The reaction mixture was warmed to about 25° C. and stirredfor about 16 h before being diluted with DCM and water. The DCM wasseparated and the aqueous layer was extracted with DCM. The combined DCMextracts were washed with brine, dried over Na₂SO₄ filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C48. Yield 1.0 g (16%). ¹H NMR (400 MHz, dmso-d₆) δ 5.61(dd, 1H), 4.22-4.27 (m, 1H), 4.14-4.15 (m, 2H), 4.05-4.08 (dd, 1H),3.79-3.81 (m, 2H), 3.40-3.45 (m, 1H), 3.25 (d, 1H), 2.15-2.20 (m, 2H),2.10 (ddd, 1H), 1.92-2.04 (m, 1H), 1.65 (s, 3H), 1.45 (s, 3H).

Step 3. Synthesis of(6R,7aS)-3,3-dimethyl-6-(tetrahydro-2H-pyran-4-yl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C49)

To a stirred solution of compound C48 (1.1 g, 4.6 mmol) in EtOAc (50 mL)was added platinum dioxide (105 mg, 0.46 mmol). The reaction mixture wasshaken under about 50 psi of hydrogen at about 25° C. for about 4 h. Themixture was filtered and the solids were washed with EtOAc. The filtratewas concentrated and the residue was purified by chromatography toprovide the title compound C49. Yield 0.75 g (68%)¹H NMR (400 MHz,dmso-d₆) δ 4.14 (m, 1H), 4.04-4.07 (dd, 1H), 3.96-4.00 (m, 2H),3.34-3.42 (m, 3H), 2.59-2.62 (m, 1H), 1.98-2.05 (m, 2H), 1.83-1.89 (m,1H), 1.65-1.66 (m, 3H), 1.44-1.61 (m, 7H).

Step 4. Synthesis of(3R,5S)-5-(hydroxymethyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-one(L30)

A solution of compound C49 (300 mg, 1.25 mmol) in acetonitrile (5 mL)and water (0.5 mL) was treated with 4-toluenesulfonic acid (11.9 mg,0.06 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL30. Yield 225 mg (90%). ¹H NMR (400 MHz, CDCl₃) δ 6.69 (s, 1H), 3.97(d, 2H), 3.65 (m, 2H), 3.47-3.36 (m, 3H), 3.07 (m, 1H), 2.48-2.43 (m,1H), 1.99-2.07 (m, 2H), 1.82-1.88 (m, 1H), 1.63-1.66 (m, 1H), 1.41-1.49(m, 3H).

Preparation 25:(3R,5S)-3-(3-fluorooxetan-3-yl)-5-(hydroxymethyl)pyrrolidin-2-one (L32)

Step 1. Synthesis of(6R,7aS)-6-(3-fluorooxetan-3-yl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C50)

DAST (0.41 mL, 2.9 mmol) was added dropwise to a solution of compoundC81 (0.51 g, 2.2 mmol) in DCM (20 mL) at about −78° C. After about 2 h,the reaction temperature was raised to about 0° C. and quenched with 50mL of about pH 7 phosphate buffer and allowed to warm to about 25° C.The DCM was separated and the aqueous layer was extracted twice withDCM. The combined DCM layers were washed with NaHCO₃, brine, dried overNa₂SO₄ filtered and concentrated. The residue was purified bychromatography to afford a sample of compound C50 (0.47 g) which wascontaminated with an olefinic by-product. To remove this olefin, thesample was dissolved in EtOH (15 mL), treated with Pearlman's catalyst(170 mg), and hydrogenated at 40 psi for about 2 h. The mixture wasfiltered and concentrated. The residue was purified by chromatography toprovide the title compound C50. Yield 0.14 g (36%)¹H NMR (400 MHz,CDCl₃) δ 4.93-5.09 (m, 2H) 4.74-4.87 (m, 1H) 4.53-4.65 (m, 1H) 4.16-4.25(m, 1H) 4.10-4.15 (m, 1H) 3.52-3.67 (m, 1H) 3.47 (t, 1H) 2.32 (ddd, 1H)1.75 (td, 1H) 1.65 (s, 3H) 1.48 (s, 3H). There was also obtained in Step1(6S,7aS)-3,3-dimethyl-6-(oxetan-3-yl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C51). ¹H NMR (400 MHz, CDCl₃) δ 4.93 (dd, 1H), 4.79 (dd, 1H), 4.60-4.68(m, 1H), 4.40 (t, 1H), 4.13-4.22 (m, 1H), 4.06-4.13 (m, 3H), 3.39-3.47(m, 1H), 3.16-3.35 (m, 2H), 2.37 (ddd, 1H), 1.60 (s, 3H), 1.46-1.56 (m,1H), 1.44 (s, 3H).

Step 2. Synthesis of(3R,5S)-3-(3-fluorooxetan-3-yl)-5-(hydroxymethyl)pyrrolidin-2-one (L32)

Compound C50 (130 mg, 0.56 mmol) was dissolved in 18 mL of acetonitrileand 2 mL of water and treated with 4-toluenesulfonic acid (5 mg, 0.03mmol). The resulting mixture was stirred at about 25° C. for about 18 h,with additional stirring at about 95° C. for about 2 h. The reactionmixture was cooled to about 25° C., concentrated, and the residue waspurified by chromatography to provide the title compound L32. Yield 68mg (64%). This was used without further characterization.

Preparation 26:(3R,5S)-3-fluoro-5-(hydroxymethyl)-3-(methoxymethyl)pyrrolidin-2-one(L33)

Step 1. Synthesis of(6R,7aS)-6-fluoro-6-(methoxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C52)

Lithium hexamethyldisilazide (1 M, 1.3 mL) was added to a solution ofcompound C37 (180 mg, 0.89 mmol) in THF (6 mL) at about 0° C. Afterabout 0 minutes, iodomethane (0.55 mL, 8.8 mmol) was added. The mixturewas allowed to warm to about 25° C. and was stirred for about 12 h.Additional lithium hexamethyldisilazide and iodomethane were added, andthe mixture was stirred for approximately another 12 h. The reaction wasthen treated with water and EtOAc. The EtOAc was separated, and theaqueous phase was extracted with EtOAc. The combined EtOAc extracts weredried over Na₂SO₄ filtered and concentrated. The residue was purified bychromatography to provide the title compound C52. Yield: 116 mg (60%).¹H NMR (400 MHz, CDCl₃) δ 4.17 (dd, 1H), 3.99 (dd, 1H), 3.64-3.78 (m,2H), 3.40-3.52 (m, 4H), 2.78 (ddd, 1H), 1.94-2.11 (m, 1H), 1.72 (s, 3H),1.49 (s, 3H).

Step 2. Synthesis of(3R,5S)-3-fluoro-5-(hydroxymethyl)-3-(methoxymethyl)pyrrolidin-2-one(L33)

Compound C52 (116 mg, 0.53 mmol) was dissolved in 18 mL of acetonitrileand 2 mL of water and treated with 4-toluenesulfonic acid (5 mg, 0.03mmol). The resulting mixture was stirred at about 25° C. for about 18 h,with additional stirring at about 95° C. for about 2 h. The reactionmixture was cooled to about 25° C., concentrated, and the residue waspurified by chromatography to provide the title compound L33. Yield: 89mg (94%). This was used without further characterization.

Preparation 27:(3R,5S)-5-(hydroxymethyl)-3-(oxetan-3-yl)pyrrolidin-2-one (L34)

Step 1. Synthesis of(3R,5S)-5-(hydroxymethyl)-3-(oxetan-3-yl)pyrrolidin-2-one (L34)

To a stirred solution of compound C51 (130 mg, 0.62 mmol) in 8 mL ofacetonitrile and 0.5 mL of water was added 4-toluenesulfonic acid (6 mg,0.03 mmol). The reaction mixture was heated at about 90° C. for about 6h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL34. Yield: 35 mg (33%). ¹H NMR (400 MHz, CDCl₃) δ 6.04 (bs, 1H), 4.91(t, 1H), 4.80 (t, 1H), 4.69 (t, 1H), 4.46 (t, 1H), 3.75-3.80 (m, 2H),3.42-3.47 (m, 1H), 3.20-3.26 (m, 1H), 2.89-2.96 (m, 1H), 2.33-2.40 (m,2H).

Preparation 28: (4R,5S)-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L36)

Step 1. Synthesis of(7R,7aS)-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (C53)

A suspension of cuprous bromide—dimethyl sulfide complex (11.9 g, 57mmol) in ether (100 mL) was cooled to about −10° C. and a solution ofmethyllithium (1.6 M, 71.4 mL, 114 mmol) was added slowly. The mixturewas then cooled to about −73° C. and TMSCl (7.18 mL, 57 mmol) was addedslowly. After the addition was complete, the mixture was maintained forabout 15 min before compound P20 (3.50 g, 23 mmol) in THF (10 mL) wasadded slowly. The mixture was maintained for approximately anotheradditional 75 min at about −78° C. before being allowed to warm to about0° C. The mixture was maintained at about 0° C. for about 45 min beforebeing treated with a mixture of saturated aqueous NH₄Cl and ammoniumhydroxide. The ethereal layer was separated and the aqueous phase wasextracted twice with EtOAc. The combined extracts were dried over MgSO₄filtered and concentrated. The residue was purified by chromatography toprovide the title compound C53. Yield: 2.27 g (59%). ¹H NMR (400 MHz,CDCl₃) δ 4.32 (dt, 1H), 3.89 (dd, 1H), 3.66-3.77 (m, 1H), 2.99 (dd, 1H),2.42-2.56 (m, 1H), 2.13 (dd, 1H), 1.65 (s, 3H), 1.47 (s, 3H), 1.02 (d,3H).

Step 2. Synthesis of (4R,5S)-5-(hydroxymethyl)-4-methylpyrrolidin-2-one(L36)

To a stirred solution of compound C53 (1.00 g, 5.9 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (8 mg,0.04 mmol). The reaction mixture was heated at about 95° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL36. Yield: 0.67 g (88%). ¹H NMR (400 MHz, CD₃OD) δ 3.53-3.71 (m, 3H),2.57-2.74 (m, 1H), 2.36 (dd, 1H), 2.10 (dd, 1H), 1.11 (d, 3H).

Synthesis of (4S,5S)-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L35)

This compound was prepared in the same manner as compound L36,substituting (S)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate(CAS 81658-27-7) for P20 in Step 1 to afford (2S,3S)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-oxopyrrolidine-1-carboxylate(C78), which was used in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 3.60 (dd,1H), 3.48 (dd, 1H), 3.27 (d, 1H), 2.55 (dd, 1H), 2.32-2.22 (m, 1H), 1.95(dd, 1H), 1.15 (d, 3H).

Synthesis of (4S,5S)-4-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (L46)

This compound was prepared in the same manner as compound L36,substituting CAS 170885-07-1 for P20, and ethylmagnesium bromide formethyllithium, in Step 1, to afford(3R,7S,7aS)-7-ethyl-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C63), which was used in step 2. ¹H NMR (400 MHz, CDCl₃) δ 3.66-3.64 (m,1H), 3.42-3.35 (m, 2H), 2.49-2.42 (m, 1H), 2.01-1.92 (m, 2H), 1.54-1.47(m, 1H), 1.39-1.32 (m, 1H), 0.88-0.84 (m, 3H).

Synthesis of (4R,5S)-4-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (L47)

This compound was prepared in the same manner as compound L36,substituting ethylmagnesium bromide for methyllithium in Step 1, toafford(7R,7aS)-7-ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C54), which was used in Step 2. ¹H NMR (400 MHz, CDCl₃) δ 4.34 (dt,1H), 3.90 (dd, 1H), 3.72 (dd, 1H), 2.91 (dd, 1H), 2.31 (dd, 1H), 2.25(m, 1H), 1.65 (s, 3H), 1.52 (d, 1H), 1.48 (s, 3H), 1.27-1.38 (m, 1H),0.92 (t, 3H).

Synthesis of (4S,5S)-5-(hydroxymethyl)-4-vinylpyrrolidin-2-one (L50)

This compound was prepared in the same manner as compound L36,substituting vinylmagnesium bromide for methyllithium in Step 1, toafford(7S,7aS)-3,3-dimethyl-7-vinyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C55), which was used in Step 2.

¹H NMR (400 MHz, CDCl₃) δ 6.84 (br. s., 1H), 5.88 (ddd, 1H), 5.18 (d,1H), 5.15 (d, 1H), 3.75 (td, 1H), 3.63-3.71 (m, 1H), 3.54-3.63 (m, 1H),3.16-3.29 (m, 2H), 2.33-2.48 (m, 2H).

Synthesis of (4R,5S)-5-(hydroxymethyl)-4-vinylpyrrolidin-2-one (L51)

This compound was prepared in the same manner as compound L36,substituting CAS 170885-07-1 for P20, and vinylmagnesium bromide formethyllithium, in Step 1. ¹H NMR (400 MHz, CDCl₃) δ 6.61 (br. s., 1H),5.74-5.91 (m, 1H), 5.06-5.20 (m, 2H), 3.80 (d, 1H), 3.46-3.62 (m, 2H),2.70-2.87 (m, 1H), 2.56 (dd, 1H), 2.30 (dd, 2H).

Synthesis of (4S,5S)-4-cyclopropyl-5-(hydroxymethyl)pyrrolidin-2-one(L58)

This compound was prepared in the same manner as compound L36,substituting cyclopropylmagnesium bromide for methyllithium in Step 1,to afford(7S,7aS)-7-cyclopropyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C56), which was used in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 3.80 (d, 2H),3.64 (dt, 1H), 2.23-2.42 (m, 2H), 1.69-1.87 (m, 1H), 0.89 (dtd, 1H),0.52 (dd, 2H), 0.04-0.23 (m, 2H).

Synthesis of (4R,5S)-5-(hydroxymethyl)-4-propylpyrrolidin-2-one (L59)

This compound was prepared in the same manner as compound L36,substituting propylmagnesium bromide for methyllithium in Step 1, toafford(7R,7aS)-3,3-dimethyl-7-propyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C57), which was used in Step 2. ¹H NMR (400 MHz, dmso-d₆) δ 7.46 (br.s, 1H), 4.63 (t, 1H), 3.44-3.36 (m, 3H), 2.37-2.31 (m, 1H), 2.07-2.01(dd, 1H), 1.95-1.89 (dd, 1H), 1.48-1.41 (m, 1H), 1.39-1.20 (m, 3H), 0.86(t, 1H).

Preparation 29:(3R,4S,5S)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L37)

Step 1. Synthesis of(6R,7S,7aS)-6-fluoro-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C58)

A solution of compound C53 (0.93 g, 5.5 mmol) in THF (22 mL) was cooledto about −78° C. and treated with LDA (2.0 M, 3.44 mL, 6.88 mmol). Themixture was maintained at about −78° C. for about 25 min before beingtreated with NFSI (2.23 g, 6.8 mmol) in THF (8 mL). After stirring atabout −78° C. for another approximate 5 min, the mixture was warmed toabout 25° C. for about 1 h. Ethyl acetate and water were added, and themixture was concentrated under reduced pressure to remove the THFpresent. The mixture was extracted twice with EtOAc, and the combinedextracts were dried over Na₂SO₄ filtered and concentrated. The residuewas purified by chromatography to provide the title compound C58. Yield:0.56 g (55%). ¹H NMR (400 MHz, CDCl₃) δ 4.58-4.77 (m, 1H), 4.54 (dtd,1H), 3.96 (dd, 1H), 3.68 (dd, 1H), 2.53-2.73 (m, 1H), 1.66 (s, 3H), 1.53(s, 3H), 1.05 (d, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −184.92. There wasalso obtained(6S,7S,7aS)-6-fluoro-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C59). Yield: 0.11 g (11%). ¹H NMR (400 MHz, CDCl₃) δ 5.25 (dd, 1H),3.95-4.10 (m, 2H), 3.71-3.82 (m, 1H), 2.86-3.03 (m, 1H), 1.68 (s, 3H),1.49 (s, 3H), 1.01 (dd, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −202.08.

Step 2. Synthesis of(3R,4S,5S)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L37)

To a stirred solution of compound C58 (590 mg, 3.1 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (27 mg,0.16 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL37. Yield: 451 mg (97%). ¹H NMR (400 MHz, CDCl₃) δ 6.94 (br. s., 1H),4.94 (dd, 1H), 3.66-3.77 (m, 2H), 3.60-3.66 (m, 1H), 2.93 (t, 1H),2.61-2.81 (m, 1H), 1.29 (d, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −194.85.

Synthesis of(3S,4S,5S)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L38)

This compound was prepared in the same manner as compound L37,substituting compound C59 for compound C58 in Step 2. ¹H NMR (400 MHz,CDCl₃) δ 6.63 (br. s., 1H), 4.86 (dd, 1H), 3.72-3.83 (m, 2H), 3.60-3.68(m, 1H), 2.67-2.80 (m, 1H), 1.96 (br. s., 1H), 1.10 (dd, 3H). ¹⁹F NMR(376 MHz, CDCl₃) δ −201.74.

Synthesis of (4R,5S)-5-(hydroxymethyl)-3,4-dimethylpyrrolidin-2-one(L48)

This compound was prepared in the same manner as compound L37,substituting iodomethane for NFSI in Step 1, to afford(7R,7aS)-3,3,6,7-tetramethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C60), which was used in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 3.75-3.50 (m,3H), 2.70-2.58 (m, 1H), 2.29-2.15 (m, 1H), 1.21-1.05 (overlapping d,6H).

Synthesis of(3S,4S,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L54)

This compound was prepared in the same manner as compound L37,substituting compound C54 for compound C53 in Step 1, to afford(6S,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C61), which was used in Step 2. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (br. s.,1H), 4.80 (dd, 1H), 3.69-3.83 (m, 2H), 3.52-3.64 (m, 1H), 3.48 (br. s,1H), 2.27-2.52 (m, 1H), 1.57-1.73 (m, 1H), 1.49 (dt, 1H), 1.04 (t, 3H).¹⁹F NMR (376 MHz, CDCl₃) δ −198.72. There was also obtained in Step 1(6R,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C62). ¹H NMR (400 MHz, CD₃CN) δ 4.78 (dd, 1H), 4.40 (dt, 1H), 3.93 (dd,1H), 3.56 (dd, 1H), 2.30-2.46 (m, 1H), 1.56 (s, 3H), 1.52 (ddd, 1H),1.42 (s, 3H), 1.35-1.48 (m, 1H), 0.97 (t, 3H).

Synthesis of(3R,4S,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L55)

This compound was prepared in the same manner as compound L37,substituting compound C62 for compound C58 in Step 2. ¹H NMR (400 MHz,dmso-d₆) δ 8.05 (br. s, 1H), 4.88 (dd, 1H), 3.48-3.46 (m, 1H), 3.41-3.38(m, 2H), 2.32-2.23 (m, 1H), 1.62-1.55 (m, 2H), 0.95 (t, 3H). ¹⁹F NMR(376 MHz, CDCl₃) δ −189.64.

Synthesis of(3R,4R,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L57)

This compound was prepared in the same manner as compound L37,substituting compound C63 for compound C53 in Step 1, to afford(3R,6R,7R,7aS)-7-ethyl-6-fluoro-3-(4-methoxy-phenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C64), which was used in Step 2. ¹H NMR (400 MHz, CDCl₃) δ 4.92 (dd,1H), 3.83-3.80 (m, 1H), 3.56-3.48 m, 2H), 2.17-2.10 (m, 1H), 1.76-1.70(m, 1H), 1.52-1.46 (m, 1H), 0.99 (t, 1H).

Synthesis of(3S,4R,5S)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L90)

This compound was prepared in the same manner as compound L37,substituting compound C78 for compound C53 in Step 1. ¹H NMR (400 MHz,CDCl₃) δ 6.82 (br. s., 1H), 4.73 (dd, 1H), 3.87 (dd, 1H), 3.56 (dd, 1H),3.28-3.37 (m, 1H), 2.24-2.37 (m, 1H), 1.21 (d, 3H).

Synthesis of(3S,4S,5S)-4-cyclopropyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L119)

This compound was prepared in the same manner as compound L37,substituting compound C56 for compound C53 in Step 1, to afford(6S,7S,7aS)-7-cyclopropyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C162), which was used in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 4.85 (dd,1H), 3.94 (dd, 1H), 3.70-3.79 (m, 1H), 3.60-3.70 (m, 1H), 1.74-1.94 (m,1H), 0.78-0.94 (m, 1H), 0.53-0.70 (m, 2H), 0.23-0.37 (m, 2H). There wasalso obtained in Step 1(6R,7S,7aS)-7-cyclopropyl-6-fluoro-3,3-dimethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C163). ¹H NMR (400 MHz, CDCl₃) δ 4.91 (d, 1H), 4.44-4.57 (m, 1H),3.94-4.09 (m, 2H), 1.70-1.76 (m, 1H), 1.67 (s, 3H), 1.54 (s, 3H),0.55-0.73 (m, 3H), 0.29-0.38 (m, 1H), 0.17-0.27 (m, 1H)

Synthesis of(3R,4S,5S)-4-cyclopropyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L120)

This compound was prepared in the same manner as compound L37,substituting compound C163 for compound C58 in Step 2. ¹H NMR (400 MHz,CD₃OD) δ 5.13 (dd, 1H), 3.86 (dd, 1H), 3.58-3.72 (m, 2H), 1.71-1.92 (m,1H), 1.08 (dtd, 1H), 0.51-0.70 (m, 2H), 0.37 (dq, 1H), 0.14-0.26 (m,1H).

Preparation 30:(4S,5S)-4-ethyl-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (L40)

Step 1. Synthesis of(7S,7aS)-7-ethyl-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C65)

A solution of compound C62 (0.80 g, 4.0 mmol) in THF (30 mL) was wastreated with LDA (2 M, 4.97 mL, 9.94 mmol) slowly at about −78° C. Themixture was kept at about −78° C. for about 45 min before the additionof a solution of NFSI (1.63 g, 5.17 mmol) in THF (10 mL). The mixturewas maintained at about −78° C. for about 15 min after the completion ofthe addition, then was warmed to about 25° C. for about 2 h. Water andEtOAc were added and the EtOAc was separated. The aqueous phase wasextracted with EtOAc, and the combined EtOAc extracts were washed withwater, brine, dried over Na₂SO₄ filtered and concentrated. The residuewas purified by chromatography to provide the title compound C65. Yield:350 mg (40%). ¹H NMR (400 MHz, dmso-d₆) δ 4.24 (dd, 1H), 4.09 (dd, 1H),3.57 (m, 1H), 2.80-2.76 (m, 1H), 1.56 (s, 3H), 1.53-1.38 (m, 2H), 1.42(s, 3H), 0.92 (t, 3H).

Step 2. Synthesis of(4S,5S)-4-ethyl-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (L40)

To a stirred solution of compound C65 (350 mg, 1.91 mmol) in 14 mL ofacetonitrile and 1.6 mL of water was added 4-toluenesulfonic acid (18mg, 0.09 mmol). The reaction mixture was heated at about 90° C. forabout 2 h. The reaction mixture was cooled to about 25° C.,concentrated, and the residue was purified by chromatography to providethe title compound L40. Yield: 260 mg (76%). ¹H NMR (400 MHz, CDCl₃) δ6.59 (br. s, 1H), 3.78-3.75 (m, 2H), 3.53-3.51 (m, 1H), 2.65-2.52 (m1H), 1.89 (br. s, 1H), 1.79-1.69 (m, 1H), 1.52-1.45 (m, 1H), 1.08 (t,3H).

Synthesis of(4S,5S)-3,3-difluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L39)

This compound was prepared in the same manner as compound L40,substituting compound C58 for compound C62 in Step 1. ¹H NMR (400 MHz,CDCl₃) δ 3.76-3.48 (m, 2H), 3.29-2.71 (m, 1H), 2.69-2.60 (m, 1H),1.18-1.06 (d, 3H).

Synthesis of(3R,4S,5S)-3-((benzyloxy)methyl)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one(L41)

This compound was prepared in the same manner as compound L40,substituting compound C58 for compound C62, and benzyloxymethyl chloride(CAS 3587-60-8) for NFSI, in Step 1 to afford a(6R,7S,7aS)-6-((benzyloxy)methyl)-6-fluoro-3,3,7-trimethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C66), which was used in Step 2. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.41 (m,5H), 4.57 (d, 2H), 3.47-3.86 (m, 5H), 2.71-2.93 (m, 1H), 1.04 (d, 3H).There was also obtained in Step 1(6S,7S,7aS)-6-((benzyloxy)methyl)-6-fluoro-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C67). ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.40 (m, 5H), 4.68 (d, 1H), 4.53(d, 1H), 4.45-4.51 (m, 1H), 3.95 (dd, 1H), 3.88 (dd, 1H), 3.59-3.74 (m,2H), 2.72-2.85 (m, 1H), 1.61 (s, 3H), 1.51 (s, 3H), 0.99 (d, 3H)

Synthesis of(3S,4S,5S)-3-((benzyloxy)methyl)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one(L42)

This compound was prepared in the same manner as compound L40,substituting compound C67 for compound C65 in Step 2. ¹H NMR (400 MHz,CDCl₃) δ 7.28-7.45 (m, 5H), 6.85 (br. s., 1H), 4.60 (s, 2H), 3.87-3.99(m, 1H), 3.65-3.86 (m, 3H), 3.44 (dd, 1H), 2.32-2.55 (m, 1H), 2.20-2.33(m, 1H).

Synthesis of(3R,4S,5S)-3-fluoro-5-(hydroxymethyl)-3,4-dimethylpyrrolidin-2-one (L44)

This compound was prepared in the same manner as compound L40,substituting compound C60 for compound C62 in Step 1, to afford(6R,7S,7aS)-6-fluoro-3,3,6,7-tetramethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C68), which was used in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 4.90-4.78 (m,2H), 3.74-3.59 (m, 1H), 2.81-2.66 (m, 1H), 1.42 (dd, 3H), (1.04 (d, 3H).There was also obtained in Step 1(6S,7S,7aS)-6-fluoro-3,3,6,7-tetramethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C69).

Synthesis of(3S,4S,5S)-3-fluoro-5-(hydroxymethyl)-3,4-dimethylpyrrolidin-2-one (L45)

This compound was prepared in the same manner as compound L40,substituting compound C69 for compound C65 in Step 2. ¹H NMR (400 MHz,CD₃OD) δ 3.59-3.56 (m, 2H), 3.46-3.44 (m, 1H), 2.41-2.22 (m, 1H),1.48-1.39 (m, 3H), 1.10-1.01 (m, 3H).

Preparation 31(4S,5S)-4-((benzyloxy)methyl)-5-(hydroxymethyl)pyrrolidin-2-one (L43)

Step 1. Synthesis of(3R,7R,7aS)-3-(4-methoxyphenyl)-7-(2-methylprop-1-en-1-yl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C70)

To a solution of cuprous bromide dimethyl sulfide (6.24 g, 30.2 mmol) inTHF (120 mL) was slowly added 2-methyl-1-propenylmagnesium bromide (0.5M, 121 60.5 mmol) at about −15° C. After about 15 min, the mixture wascooled to about −78° C. A solution of CAS 170885-07-1 (1.4 g, 6.0 mmol)and TMSCl (1.3 g, 12.1 mmol) in THF (25 mL) was added over about 15 min.After about 1 h, aqueous NH₄Cl was added to the mixture and it wasallowed to warm to about 25° C. Ethyl acetate was added and the EtOAcwas separated, dried over Na₂SO₄ filtered and concentrated. The residuewas purified by chromatography to provide the title compound C70. Yield:1.1 g (64.0%). ¹H NMR (400 MHz, dmso-d₆) δ 7.30 (d, 2H), 6.92 (d, 2H),6.05 (s, 1H), 5.27 (dt, 1H), 4.13 (dd, 1H), 3.87-3.94 (m, 1H), 3.74 (s,3H), 3.59-3.65 (m, 1H), 3.15-3.25 (m, 1H), 2.55-2.65 (m, 1H), 2.46-2.52(s, 1H), 1.67 (d, 3H), 1.61 (d, 3H).

Step 2. Synthesis of(3R,7S,7aS)-7-(hydroxymethyl)-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C71)

A solution of compound C70 (1.1 g, 3.8 mmol) in DCM (20 mL) was treatedwith ozone at about −78° C. Once excess ozone was present, methylsulfide (5 mL) was added slowly. The mixture was stirred at about −78°C. for about 1 hour before being evaporated to dryness. The residue wasdissolved in 9 mL of THF and 1 mL of water and treated with NaBH₄ (307mg, 7.6 mmol). The mixture was stirred for about 2 h at about 25° C.before being treated with aqueous NH₄Cl and EtOAc. The EtOAc extractswere dried over Na₂SO₄ filtered and concentrated. The residue waspurified by chromatography to provide the title compound C71. Yield: 460mg (46%). ¹H NMR (400 MHz, dmso-d₆) δ 7.29 (d, 2H), 6.93 (d, 2H), 6.03(s, 1H), 4.87 (t, 1H), 4.15 (dd, 1H), 3.89-3.97 (m, 1H), 3.75 (s, 3H),3.40-3.55 (m, 3H), 2.39-2.55 (m, 3H).

Step 3. Synthesis of(4S,5S)-4-((benzyloxy)methyl)-5-(hydroxymethyl)pyrrolidin-2-one (L43)

A solution of compound C71 (220 mg, 0.84 mmol) in DMF (4.2 mL) wascooled to about 0° C. and treated with sodium hydride (60%, 40 mg, 1.0mmol) followed by (bromomethyl)benzene (0.11 mL, 0.92 mmol). The mixturewas kept for about 1 h at about 0° C. before being diluted with water.The mixture was extracted with EtOAc. The extracts were dried overNa₂SO₄ filtered and concentrated. The residue was subjected to treatmentwith 4-toluenesulfonic acid in acetonitrile and water to provide thetitle compound L43. Yield: 100 mg (51%). ¹H NMR (400 MHz, dmso-d₆) δ7.52 (s, 1H), 7.26-7.39 (m, 5H), 4.77 (t, 1H), 4.48 (s, 2H), 3.35-3.46(m, 3H), 3.26-3.35 (m, 2H), 2.33-2.42 (m, 1H), 2.24-2.33 (m, 1H),1.85-1.95 (m, 1H).

Preparation 32:(4S,5S)-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one (L49)

Step 1. Synthesis of(3R,7S,7aS)-7-(fluoromethyl)-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C72)

A solution of compound C71 (460 mg, 1.75 mmol) and 2,6-lutidine (468 mg,4.37 mmol) in DCM at about 0° C. was treated with DAST (563 mg, 3.5mmol). The mixture was stirred at about 25° C. for about 5 h beforebeing quenched with saturated aqueous NaHCO₃ and extracted with DCM. Thecombined DCM extracts dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC72. Yield: 410 mg (88%). LCMS: m/z, 265.3 (M+1), retention time: 1.602min.

Step 2. Synthesis of(4S,5S)-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one (L49)

To a stirred solution of compound C71 (100 mg, 0.38 mmol) in 9 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (3 mg,0.02 mmol). The reaction mixture was heated at about 90° C. until thesolvent was evaporated. Additional acetonitrile and water were added andthe operation was repeated several more times. The reaction mixture wascooled to about 25° C., concentrated, and the residue was purified bychromatography to provide the title compound L49. Yield: 50 mg (90%). ¹HNMR (400 MHz, CD₃OD) δ 4.53-4.51 (m, 1H), 4.41-4.40 (m, 1H), 3.66-3.53(m, 3H), 2.65-2.54 (m, 2H), 2.21-2.16 (m, 1H).

Preparation 33:(3S,4S,5S)-4-(fluoromethyl)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one(L52)

Step 1. Synthesis of(3R,7S,7aS)-7-(fluoromethyl)-3-(4-methoxyphenyl)-6-methyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C73)

To a solution of compound C73 (160 mg, 0.61 mmol) in THF (3 mL) at about−78° C. was added LDA (2 M, 0.38 mL). The mixture was stirred for about0.5 h before iodomethane (107 mg, 0.76 mmol) was added. The mixture wasmaintained for about 10 min at about −78° C. before it was warmed toabout 25° C. and stirred for about 1 h. EtOAc and water were added andthe mixture was extracted with EtOAc. The combined EtOAc extracts weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography to provide the title compound C73. Yield: 140 mg(82%). LCMS: m/z, 279 (M+1), retention time: 1.244 min

Step 2. Synthesis of(3S,4S,5S)-4-(fluoromethyl)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one(L52)

A solution of compound C73 (140 mg, 0.5 mmol) in 6.5 mL of AcOH and 3.5mL of water was heated to about 90° C. for about 40 min before beingevaporated to dryness. The residue was dissolved in 25 mL of MeOH andconcentrated. The residue was purified by chromatography to provide thetitle compound L52. Yield: 70 mg (87%). ¹H NMR (400 MHz, CD₃OD) δ4.62-4.51 (d, 2H), 3.71-3.68 (m, 1H), 3.54 (m, 2H), 2.41-2.39 (m, 1H),2.23-2.10 (m, 1H), 1.25 (s, 3H).

Preparation 34:(3R,4R,5R)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L53)

Step 1. Synthesis of(7aR)-3,3-dimethyl-6-(phenylselanyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C74)

LDA (2 M, 41.9 mL) was added to a solution of(R)-3,3-dimethyltetraz-hydropyrrolo[1,2-c]oxazol-5(1H)-one (CAS103630-36-0, 10 g, 64.4 mmol) in THF (130 mL) at about −78° C. Afterabout 30 min, diphenyl diselenide (24.13 g, 77.3 mmol) in THF (125 mL)was added. The mixture was kept at about −78° C. for about 30 min beforebeing warmed to about 25° C. for about 1 h. Ethyl acetate and water wereadded, and the mixture was partially concentrated before being extractedwith EtOAc. The combined EtOAc extracts were dried over Na₂SO₄, filteredand concentrated. The residue was purified by chromatography to providethe title compound C74. Yield: 12.0 g (60%). ¹H NMR (400 MHz, CDCl₃) δ7.72-7.64 (m, 2H), 7.38-7.27 (m, 3H), 4.27 (dd, 1H), 4.12-4.07 (m, 1H),3.98-3.92 (m, 2H), 3.72-3.64 (m, 1H), 3.31 (t, 1H), 3.13 (t, 1 H),2.59-2.53 (m, 1H), 2.33 (dd, 2H), 1.84-1.75 (m, 1H), 1.62 and 1.56 (s,3H), 1.59 (s, 3H), 1.44 and 1.28 (s, 3H).

Step 2. Synthesis of(R)-3,3-dimethyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one (C75)

A solution of compound C74 (12.0 g, 38.7 mmol) in DCM (150 mL) andpyridine (6.8 mL) at about 0° C. was treated with 30% hydrogen peroxidesolution (17.86 mL, 128 mmol). The mixture was kept at about 0° C. forabout 30 min before being warmed slowly to about 25° C. After about 3 h,the mixture was diluted with DCM (100 mL) and washed with saturatedaqueous NaHCO₃ solution. The DCM extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C75. Yield: 4.0 g (68%). ¹HNMR (400 MHz, CDCl₃) δ 7.06 (dd, 1H), 6.09 (dd, 1H), 4.66-4.62 (m, 1H),4.12 (dd, 1H), 3.33 (dd, 1H), 1.67 (s, 3H), 1.55 (s, 3H).

Step 3. Synthesis of(7S,7aR)-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (C76)

Methyllithium (1.6 M, 34.7 mL) was added to a suspension of cuprousbromide—dimethylsulfide complex (5.7 g, 27.8 mmol) in diethyl ether (40mL) at about −10° C. After the addition was complete, the solution wascooled to about −78° C. After about 10 min, TMSCl (3.5 mL, 27.7 mmol)was added, followed by a solution of compound C75 (1.7 g, 11.1 mmol) inTHF (28 mL). The mixture was stirred at about −78° C. for about 2 h.then was allowed to warm to about 20° C. for about 1 h. A mixture ofaqueous NH₄Cl and ammonium hydroxide was added with stirring, afterwhich the mixture was diluted with EtOAc. The EtOAc was separated andthe aqueous phase was extracted with EtOAc. The combined EtOAc extractswere washed with water, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C76. Yield: 1.75 g (93%). ¹H NMR (400 MHz, CDCl₃) δ4.33-4.28 (m, 1H), 3.86 (dd, 1H), 3.71 (t, 1H), 2.97 (dd, 1H), 2.50-2.43(m, 1H), 2.11 (d, 1H), 1.63 (s, 3H), 1.45 (s, 3H), 1.01 (d, 3H).

Step 4. Synthesis of(6R,7R,7aR)-6-fluoro-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C77)

LDA (1.8 M, 7.03 mL) was added to a −78° C. solution of compound C76(1.427 g, 8.4 mmol) in THF (27 mL). After about 1 h, a solution of NFSI(3.43 g, 10.5 mmol) in THF (8 mL) was added. After about 5 min, themixture was allowed to warm to about 25° C. After about 3 h, EtOAc andwater were added, and the mixture was partially concentrated beforebeing extracted with EtOAc. The combined EtOAc extracts were dried overMgSO4, filtered, and concentrated. The residue was dissolved in DCM andfiltered. The filtrate was concentrated and the residue was purified bychromatography to provide the title compound C77. Yield: 282 mg (18%).¹H NMR (400 MHz, CD₃CN) δ 5.27 (dd, 1H), 3.99-4.08 (m, 1H), 3.95 (dd,1H), 3.72 (t, 1H), 2.94 (quind, 1H), 1.58 (s, 3H), 1.39 (s, 3H), 0.90(dd, 3H).

Step 5. Synthesis(3R,4R,5R)-3-fluoro-5-(hydroxymethyl)-4-methylpyrrolidin-2-one (L53)

To a stirred solution of compound C77 (280 mg, 1.5 mmol) in 9 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (15 mg0.07 mmol). The reaction mixture was heated at about 90° C. for about1.5 h. The reaction mixture was cooled to about 25° C., concentrated,and the residue was purified by chromatography to provide the titlecompound L53. Yield: 169 mg (77%). ¹H NMR (400 MHz, CD₃CN) S 6.56 (br.s, 1H), 4.83 (dd, 1H), 3.52-3.67 (m, 2H), 3.37-3.50 (m, 1H), 2.83-2.94(m, 1H), 2.63-2.80 (m, 1H), 0.98 (dd, 3H).

Preparation 35:(3S,4S,5S)-4-ethyl-d₅-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L56)

Step 1. Synthesis of(7R,7aS)-7-ethyl-d₅-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C79)

A solution of perdeuteroethylmagnesium bromide was prepared from 11.06 g(97 mmol) of ethyl-d5 bromide and magnesium metal (2.73 g, 112 mmol) in80 mL of THF. A portion of this solution (43.5 mL) was added to asuspension of cuprous bromide—dimethyl sulfide complex (6.78 g, 32.6mmol) complex in THF (40 mL) at about −10° C. The mixture was stirred atabout −10° C. for about 10 min before being cooled to about −78° C.Chlorotrimethylsilane (3.55 g, 32.6 mmol) was added. After about 15 min,compound P20 (2.0 g, 13.1 mmol) in THF (20 mL) was added. The mixturewas kept at about −78° C. for about 30 min before being warmed to about25° C. for about 18 h. A mixture of aqueous NH₄Cl and ammonium hydroxidewas added with stirring, after which the mixture was diluted with EtOAcand filtered. The EtOAc was separated and the aqueous phase wasextracted with EtOAc. The combined EtOAc extracts were washed withNaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography to provide the title compound C79. Yield:850 mg (35%). ¹H NMR (400 MHz, CDCl₃) δ 4.34 (dt, 1H), 3.90 (dd, 1H),3.68-3.75 (m, 1H), 2.91 (dd, 1H), 2.31 (dd, 1H), 2.24 (t, 1H), 1.65 (s,3H), 1.48 (s, 3H).

Step 2. Synthesis of(6S,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C80)

A solution of compound C79 (512 mg, 2.7 mmol) in 2-methylTHF (12.5 mL)was treated at about −78° C. with lithium hexamethyldisilazide (1 M, 3.0mL) and the mixture was kept for about 45 min at about −78° C. beforebeing added into an approximate −78° C. solution of NSFI (1.12 g, 3.54mmol) in 2-methylTHF (12.5 mL). The mixture was kept at about −78° C.for about 30 min, then water (10 mL) and EtOAc (10 mL) were added. TheEtOAc was separated and the aqueous phase was extracted with EtOAc (10mL). The combined EtOAc extracts were washed with sodium iodidesolution, sodium thiosulfate solution, NaOH solution, brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C80. Yield: 94 mg (17%). ¹HNMR (400 MHz, CD₃CN) δ 5.26 (dd, 1H), 3.95-4.08 (m, 2H), 3.61-3.71 (m,1H), 2.62-2.75 (m, 1H), 1.58 (s, 3H), 1.40 (s, 3H).

Step 3. Synthesis of(3S,4S,5S)-4-ethyl-d₅-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L56)

To a stirred solution of compound C80 (94 mg, 0.46 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (4 mg,0.02 mmol). The reaction mixture was heated at about 90° C. for about 4h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL56. Yield: 51 mg (67%). ¹H NMR (400 MHz, CD₃CN) δ 6.76 (br. s., 1H),4.73 (dd, 1H), 3.57-3.67 (m, 2H), 3.32-3.42 (m, 1H), 2.85 (t, 1H), 2.40(dt, 1H).

Preparation 36:(4R,5S)-5-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-2-one (L60)

Step 1. Synthesis of(7R,7aS)-7-(hydroxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C82)

A stream of ozonized oxygen was bubbled through a solution of compoundC55 (1.95 g, 10.8 mmol) in DCM (49 mL) and MeOH (16 mL) at about −78° C.for about 2 h. Dimethyl sulfide (10 mL) was added at about −78° C.,followed NaBH₄ (2.44 g, 64.6 mmol) at the same temperature. After about30 min, the reaction was warmed to about 0° C. and stirred for about 2h. Ethyl acetate was added, and the mixture was washed with water, thenbrine. The combined EtOAc extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C82. Yield: 1.2 g (60%). ¹H NMR (400 MHz, CDCl₃) δ4.40-4.34 (m, 1H), 3.97 (dd, 1H), 3.86 (dd, 1H), 3.72-3.62 (m, 2H), 2.94(dd, 1H), 2.58-2.53 (m, 1H), 2.25 (d, 1H), 1.64 (s, 3H), 1.45 (s, 3H).

Step 2. Synthesis of(7R,7aS)-7-(methoxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C83)

To a stirred solution of compound C55 (1.4 g, 7.5 mmol) in THF (40 mL)was added freshly prepared silver(I) oxide (17.48 g, 75.7 mmol),followed by iodomethane (5.37 g, 37.8 mmol). The mixture was heated atabout 70° C. for about 16 h. The mixture was then cooled to about 25°C., filtered and concentrated. The residue was purified bychromatography to provide the title compound C83. Yield: 1.1 g (73%). ¹HNMR (400 MHz, CDCl₃) δ 4.36-4.30 (m, 1H), 3.92 (dd, 1H), 3.68 (dd, 1H),3.39-3.25 (m, 2H), 3.30 (s, 3H), 2.93 (dd, 1H), 2.61-2.53 (m, 1H), 2.22(dd, 1H), 1.62 (s, 3H), 1.46 (s, 3H).

Step 3. Synthesis of(4R,5S)-5-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-2-one (L60)

To a stirred solution of compound C83 (200 mg, 1.0 mmol) in 18.8 mL ofacetonitrile and 2.1 mL of water was added 4-toluenesulfonic acid (9 mg,0.05 mmol). The reaction mixture was heated to reflux for about 2 h. Thereaction mixture was cooled to about 25° C., concentrated, and theresidue was purified by chromatography to provide the title compoundL60. Yield: 150 mg (93%). ¹H NMR (400 MHz, dmso-d₆) δ 3.49-3.34 (m, 5H),3.32 (s, 3H), 3.23 (s, 3H), 2.73-2.60 (m, 1H), 2.09-1.95 (m, 2H).

Preparation 37:(4R,5S)-3-fluoro-5-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-2-one(L61) Step 1. Synthesis of(7R,7aS)-6-fluoro-7-(methoxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C84)

A solution of compound C83 (250 mg, 1.3 mmol) in THF (10 mL) was treatedwith lithium hexamethyldisilazide (1 M, 2.13 mL) at −78° C. and kept forabout 30 min before the addition of a solution of NFSI (436 mg, 1.4mmol) in THF (10 mL). The mixture was maintained for about 30 min atabout −78° C. and then was allowed to warm to about 25° C. for about 1h. Water and EtOAc were added and the phases were separated. The EtOAcextract EtOAc extracts were washed with sodium iodide solution, sodiumthiosulfate solution, NaOH solution, brine, dried over Na₂SO₄, filteredand concentrated. The residue was purified by chromatography to providethe title compound C84. Yield: 90 mg (33%). ¹H NMR (400 MHz, CDCl₃) δ4.88 (d, 1H), 4.51-4.46 (m, 1H), 3.96 (dd, 1H), 3.70 (dd, 1H), 3.49-3.44(m, 2H), 3.31 (s, 3H), 2.74-2.63 (m, 1H), 1.63 (s, 3H), 1.46 (s, 3H).There was also obtained(7R,7aS)-6,6-difluoro-7-(methoxymethyl)-3,3-dimethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C85). Yield 45 mg (15%). ¹H NMR (400 MHz, CDCl₃) δ 4.24-4.19 (m, 1H),4.08 (dd, 1H), 3.79 (dd, 1H), 3.55 (dd, 1H), 3.48 (dd, 1H), 3.30 (s,3H), 2.94-2.85 (m, 1H), 1.65 (s, 3H), 1.53 (s, 3H).

Step 2. Synthesis of(7R,7aS)-6-fluoro-7-(methoxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C86)

A solution of compound C84 (125 mg, 0.575 mmol) in THF (10 mL) wastreated with potassium hexamethyldisilazide (1 M, 0.115 mL) at about 0°C. After about 5 min, the mixture was allowed to warm to about 25° C.for about 2 h. Aqueous sodium dihydrogen phosphate was added and themixture was extracted with EtOAc. The combined EtOAc extracts werewashed with water, brine, dried over Na₂SO₄, filtered and concentratedto provide the title compound C86. Yield: 115 mg (92%). ¹H NMR (400 MHz,CDCl₃) δ 5.28 (dd, 1H, diastereomer 1), 4.89 (d, 1H, diastereomer 2),4.51-4.47 (m, 1H, diastereomer 2), 4.07-4.01 (m, 2H, diastereomer 1),3.96 (dd, 1H, diastereomer 2), 3.83-3.78 (m, 1H, diastereomer 1), 3.70(dd, 1H, diastereomer 2), 3.57-3.53 (m, 1H, diastereomer 1), 3.49-3.44(m, 2H, diastereomer 2), 3.47-3.43 (m, 1H, diastereomer 1), 3.31 (s, 3H,diastereomer 2), 3.30 (s, 3H, diastereomer 1), 3.04-3.00 (m, 1H,diastereomer 1), 2.74-2.63 (m, 1H, diastereomer 2), 1.67 (s, 3H,diastereomer 1), 1.63 (s, 3H, diastereomer 2), 1.49 (s, 3H, diastereomer1), 1.46 (s, 3H, diastereomer 2).

Step 3. Synthesis of(4R,5S)-3-fluoro-5-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-2-one

(L61) To a stirred solution of compound C86 (130 mg, 0.6 mmol) in 10 mLof acetonitrile and 0.6 mL of water was added 4-toluenesulfonic acid (6mg, 0.03 mmol). The reaction mixture was heated at about 90° C. forabout 2 h. The reaction mixture was cooled to about 25° C.,concentrated, and the residue was purified by chromatography to providethe title compound L61. Yield: 80 mg (76%). ¹H NMR (400 MHz, CDCl₃) δ5.12 (dd, 1H, diastereomer 1), 4.94 (dd, 1H, diastereomer 2), 3.85-3.54(m, 10H, diastereomers 1 and 2), 3.42 (s, 3H, diastereomer 1), 3.37 (s,3H, diastereomer 2), 2.95-2.84 (m, 2H, diastereomers 1 and 2).

Synthesis of(4R,5S)-3,3-difluoro-5-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-2-one(L63)

This compound was prepared in the same manner as compound L61,substituting compound C85 for compound C86 in Step 3. ¹H NMR (400 MHz,CDCl₃) δ 3.88-3.81 (m, 2H), 3.75-3.71 (m, 1H), 3.66-3.61 (m, 2H), 3.39(s, 3H), 3.05-2.95 (m, 1H).

Preparation 38:(3S,4S,5S)-4-ethyl-5-(hydroxymethyl)-3-methoxypyrrolidin-2-one (L66)

Step 1. Synthesis of(7S,7aS)-7-ethyl-6-hydroxy-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C87)

A solution of compound C54 (1.0 g, 5.5 mmol) in THF (25 mL) was treatedwith LDA (3.4 mL, 6.8 mmol) at about −78° C. The mixture was kept forabout 20 min and then treated with a solution of(1R)-(−)-(10-camphorsulfonyl)oxaziridine (CAS 104372-31-8, 1.50 g, 6.5mmol) in THF (5 mL). After about 30 min, the mixture was allowed to warmto about 25° C. for about 30 min. Methanol (2 mL) was added and themixture was concentrated. The residue was purified by chromatography toprovide the title compound C87. Yield: 800 mg (73%). This was used inthe next step without further characterization.

Step 2. Synthesis of(6S,7S,7aS)-7-ethyl-6-methoxy-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C88)

To a stirred solution of compound C87 (800 mg, 4.0 mmol) in THF (50 mL)was added freshly prepared silver(I) oxide (9.3 g, 40.2 mmol), followedby iodomethane (1.25 ml, 20.1 mmol). The mixture was heated at about 75°C. for about 16 h. The mixture was then cooled to about 25° C., filteredand concentrated. The residue was purified by chromatography to providethe title compound C88. Yield: 180 mg (21%). ¹H NMR (400 MHz, CDCl₃) δ4.09 (d, 1H), 4.04-3.96 (m, 2H), 3.70-3.66 (m, 1H), 3.55 (s, 3H),2.52-2.50 (m, 1H), 1.69-1.64 (m, 1H), 1.62 (s, 3H), 1.48-1.41 (m, 1H),1.47 (s, 3H), 0.90 (t, 3H). There was also obtained(6R,7S,7aS)-7-ethyl-6-methoxy-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C89). Yield: 375 mg (44%). ¹H NMR (400 MHz, CDCl₃) δ 4.44-4.40 (m, 1H),3.92-3.89 (m, 1H), 3.66 (s, 1H), 3.64-3.59 (m, 1H), 3.53 (s, 3H),2.17-2.12 (m, 1H), 1.62 (s, 3H), 1.50-1.41 (m, 1H), 1.48 (s, 3H),1.38-1.30 (m, 1H), 0.97 (t, 3H).

Step 3. Synthesis of(3S,4S,5S)-4-ethyl-5-(hydroxymethyl)-3-methoxypyrrolidin-2-one (L66)

To a stirred solution of compound C88 (180 mg, 0.8 mmol) in 9 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (7 mg,0.04 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL66. Yield: 75 mg (51%). ¹H NMR (400 MHz, CDCl₃) δ 6.09 (br, 1H),3.68-3.64 (m, 2H), 3.61 (s, 3H), 3.57 (d, 1H), 3.48 (br. s, 1H), 2.84(br. s, 1H), 2.42-2.30 (m, 1H), 1.64-1.58 (m, 1H), 1.47-1.33 (m, 1H),0.97 (t, 3H).

Synthesis of(3R,4S,5S)-4-ethyl-5-(hydroxymethyl)-3-methoxypyrrolidin-2-one (L67)

This compound was prepared in the same manner as compound L66,substituting compound C89 for compound C88 in Step 3. ¹H NMR (400 MHz,CDCl₃) δ 6.10 (br. s, 1H), 3.75-3.70 (m, 2H), 3.63 (s, 3H), 3.62-3.60(m, 2H), 2.35-2.27 (m, 1H), 2.12 (br. s, 1H), 1.73-1.64 (m, 1H),1.61-1.52 (m, 1H), 1.00 (t, 3H).

Synthesis of(3S,4S,5S)-5-(hydroxymethyl)-3-methoxy-4-methylpyrrolidin-2-one (L64)

This compound was prepared in the same manner as compound L66,substituting compound C53 for compound C54 in Step 1 to afford(7S,7aS)-6-hydroxy-3,3,7-trimethyltetrahydro-pyrrolo[1,2-c]oxazol-5(3H)-one(C90). Application of Step 2 to compound C90 afforded(6S,7S,7aS)-6-methoxy-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C91) and(6R,7S,7aS)-6-methoxy-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C92). Application of Step 3 to compound C91 afforded the title compoundL64. ¹H NMR (400 MHz, CDCl₃) δ 3.65-3.62 (m, 4H), 3.59 (s, 3H), 3.48(br. s, 1H), 2.69-2.64 (m, 1H), 1.01 (d, 3H).

Synthesis of(3R,4S,5S)-5-(hydroxymethyl)-3-methoxy-4-methylpyrrolidin-2-one (L65)

This compound was prepared in the same manner as compound L64,substituting compound C92 for compound C91 in Step 3. ¹H NMR (400 MHz,CDCl₃) δ 6.37 (br. s, 1H), 3.74-3.64 (m, 3H), 3.63 (s, 3H), 3.58-3.55(m, 1H), 2.53-2.47 (m, 1H), 2.45 (br. s, 1H), 1.20 (d, 3H).

Synthesis of(4S,5S)-3-(benzyloxy)-4-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (L68)

This compound was prepared in the same manner as compound L66,substituting (bromomethyl)benzene for iodomethane in Step 2 and usingthe resulting mixture of diastereomers in Step 3. ¹H NMR (400 MHz,CDCl₃) δ 7.39-7.26 (m, 5H, both diastereomers), 6.27 (br. s, 1H, bothdiastereomers), 5.15 (d, 1H, diastereomer 1), 5.01 (d, 1H, diastereomer2), 4.71 (d, 1H, both diastereomers), 3.93 (d, 1H, diastereomer 1), 3.78(d, 1H, diastereomer 2), 3.69-3.60 (m, 3H, both diastereomers),2.40-2.32 (m, 1H, both diastereomers), 1.69-1.63 (m, 1H, bothdiastereomers), 1.54-1.40 (m, 1H, both diastereomers), 0.98 (t, 3H,diastereomer 1), 0.92 (t, 3H, diastereomer 2).

Preparation 39: tert-butyl((4S,5S)-4-ethyl-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate (L70)

Step 1. Synthesis of(7S,7aS)-6-azido-7-ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C93)

LDA (2.0 M, 1.7 mL) was added to a solution of compound C54 (500 mg, 2.7mmol) in THF (20 mL) at about −78° C. After about 30 minutes at about−78° C., a 10% solution 2,4,6-triisopropylbenzenesulfonyl azide (CAS36982-84-0, 2.0 mL, 0.66 mmol) was added. After stirring at about −78°C. for about 10 min, the solution was allowed to warm to about 25° C.for about 1 h.

Aqueous NH₄Cl solution was added and the mixture was extracted withEtOAc. The EtOAc extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C93. Yield: 500 mg (82%). ¹H NMR (400 MHz, CDCl₃) δ 4.43(d, 1H), 4.13-4.08 (m, 1H), 4.00-3.97 (m, 1H), 3.70-3.65 (m 1H),2.49-2.47 (m, 1H), 1.65 (s, 3H), 1.75-1.42 (m, 2H), 1.47 (s, 3H), 0.90(t, 3H).

Step 2. Synthesis of(7R,7aS)-6-amino-7-ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C94)

To a solution of compound C93 (500 mg, 2.2 mmol) in MeOH (30 mL) wasadded palladium on carbon (100 mg) and the mixture was stirred under ahydrogen atmosphere (1 atm) for about 16 h. The mixture was filtered andthe filtrate was concentrated to provide the title compound C94. Yield:380 mg (86%). This was used in the next step without furthercharacterization.

Step 3. Synthesis of(4R,5S)-3-amino-4-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (C95)

To a stirred solution of compound C94 (380 mg, 1.9 mmol) in 27 mL ofacetonitrile and 3 mL of water was added 4-toluenesulfonic acid (0.40 g,2.3 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C. and concentrated toprovide the title compound C95. Yield: 300 mg (47%). ¹H NMR (400 MHz,dmso-d₆) δ 7.47 (d, 2H), 7.11 (d, 2H), 4.13-4.10 (m, 1H), 3.71-3.56 (m,2H), 3.46-3.43 (m, 1H), 2.07 (s, 3H), 2.06-1.91 (m, 1H), 1.50-1.47 (m,1H), 1.39-1.35 (m, 1H), 0.92 (t, 3H).

Step 4. Synthesis of tert-butyl((4S,5S)-4-ethyl-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate (L70)

To a solution of compound C95 (300 mg, 1.9 mmol) and Et₃N (0.78 mL, 5.7mmol) in THF (10 mL) and water (10 mL) was added di-t-butyl dicarbonate(0.83 mL, 3.8 mmol). The mixture was kept at about 25° C. for about 16h. The reaction mixture was concentrated and the residue was purified bychromatography to provide the title compound L70. Yield: 280 mg (ca.100%). ¹H NMR (400 MHz, dmso-d₆) δ 7.76 (br. s, 1H), 6.37 (d, 1H), 5.44(t, 1H), 4.07-3.93 (m, 1H), 3.48-3.43 (m, 2H), 3.37 (br. m, 1H),2.36-2.33 (m, 1H), 1.55-1.45 (m, 1H), 1.37 (s, 9H), 1.33-1.28 (m, 1H),0.83 (t, 3H).

Preparation 40:(1R,4S,5S,6S)-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L74) Step 1. Synthesis of(3R,5aR,6S,6aS,6bS)-3-(4-methoxyphenyl)-6-methyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C96)

To a stirred suspension of methyldiphenylsulfonium tetrafluoroborate(CAS 893-69-6, 31.36 g, 104 mmol) in THF (200 mL) was added LDA (2 M, 65mL, 130 mmol) slowly at about −78° C. The reaction mixture was kept atabout −78° C. for about 1.5 h, at which point a solution of(3R,7aS)-3-(4-methoxyphenyl)-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one(CAS 170885-07-1, 12.0 g, 51.9 mmol) in THF (90 mL) was added slowly.The reaction mixture was maintained at about −78° C. for about 1.5 h andthen allowed to warm to about 25° C. It was stirred for about 1.5 h atabout 25° C. before being quenched with EtOAc and NaHCO₃ solution. TheEtOAc was separated, and the aqueous phase was back extracted withEtOAc. The combined EtOAc extracts were dried over Na₂SO₄ filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C96. Yield 6.5 g (48%). ¹H NMR (400 MHz, CDCl₃): δ 7.27(d, 2H), 6.84 (d, 2H), 6.23 (s, 1H), 4.14 (dd, 1H), 3.88 (dd, 1H), 3.78(s, 3H), 3.38 (dd, 1H), 1.88-1.86 (m, 1H), 1.79-1.77 (m, 1H), 1.51-1.47(m, 1H), 1.14 (d, 3H). There was also obtained(3R,5aR,6R,6aS,6bS)-3-(4-methoxyphenyl)-6-methyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C97). Yield: 1.5 g (11%). ¹H NMR (400 MHz, CDCl₃): δ 7.29 (d, 2H), 6.85(d, 2H), 6.26 (s, 1H), 4.20 (t, 1H), 3.78 (s, 3H), 3.70 (t, 1H), 3.53(dd, 1H), 2.12-2.06 (m, 2H), 1.61-1.55 (m, 1H), 1.26 (d, 3H).

Step 2. Synthesis of(1R,4S,5S,6S)-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L74)

To a stirred solution of compound C96 (1.7 g, 6.6 mmol) in 45 mL ofacetonitrile and 5 mL of water was added 4-toluenesulfonic acid (64 mg,0.33 mmol). The reaction mixture was heated at about 90° C. for about 45min. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL74. Yield: 0.83 g (90%). ¹H NMR (400 MHz, CD₃OD) δ 3.40-3.59 (m, 3H),1.71 (dd, 1H), 1.57 (dt, 1H), 1.13 (d, 3H), 1.02 (dd, 1H).

Synthesis of(1R,4S,5S,6R)-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L75)

This compound was prepared in the same manner as compound L74,substituting compound C97 for compound C96 in Step 2. ¹H NMR (400 MHz,CD₃CN) δ 6.12 (br. s., 1H), 3.45-3.54 (m, 2H), 3.35 (br. s, 1H),3.26-3.33 (m, 1H), 1.69-1.80 (m, 2H), 1.23-1.39 (m, 1H), 1.02 (d, 3H).

Synthesis of (1R,4S,5S)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L72)

This compound was prepared in the same manner as compound L74,substituting(3R,5aR,6aS,6bS)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(CAS 187742-05-8) for compound C96 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ3.47-3.61 (m, 3H), 1.97 (ddd, 1H), 1.75-1.86 (m, 1H), 1.19 (td, 1H),0.59-0.68 (m, 1H).

Synthesis of(1S,4S,5R)-4-(hydroxymethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one(L73)

This compound was prepared in the same manner as compound L74,substituting (1-methyl)ethyldiphenylsulfonium tetrafluoroborate (CAS40447-58-3) for CAS 893-69-6 in Step 1. ¹H NMR (400 MHz, CDCl₃) δ 7.04(br. s., 1H), 3.88 (br. s., 1H), 3.61-3.70 (m, 1H), 3.48-3.61 (m, 1H),3.44 (d, 1H), 1.70 (d, 1H), 1.51 (d, 1H), 1.10 (s, 3H), 1.10 (s, 3H).

Synthesis of(1R,4S,5S,6S)-6-ethyl-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L76)

This compound was prepared in the same manner as compound L74,substituting propyldiphenylsulfonium tetrafluoroborate (CAS 14264-05-2)for CAS 893-69-6 in Step 1 to afford(3R,5aR,6S,6aS,6bS)-6-ethyl-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo-[1,2-c]oxazol-5(3H)-one(C98), which was used in Step 2. ¹H NMR (400 MHz, CDCl₃) δ 6.56 (br. s.,1H), 3.63-3.69 (m, 1H), 3.62 (d, 1H), 3.49-3.56 (m, 1H), 3.48 (br. s,1H), 1.63 (ddd, 1H), 1.55 (ddd, 1H), 1.29-1.39 (m, 2H), 0.99 (t, 3H),0.95-1.05 (m, 1H). There was also obtained in Step 1(3R,5aR,6R,6aS,6bS)-6-ethyl-3-(4-methoxyphenyl)-tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C99). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, 2H), 6.88 (d, 2H), 6.28 (s,1H), 4.22 (dd, 1H), 3.81 (s, 3H), 3.73 (dd, 1H), 3.53 (dd, 1H), 2.14 (d,2H), 1.57-1.67 (m, 2H), 1.51 (dd, 1H), 1.08 (t, 3H).

Synthesis of(1R,4S,5S,6R)-6-ethyl-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L77)

This compound was prepared in the same manner as compound L74,substituting compound C99 for compound C96 in Step 2. ¹H NMR (400 MHz,CDCl₃) δ 6.99 (br. s, 1H), 4.41 (br. s., 1H), 3.68 (dd, 1H), 3.57 (dd,1H), 3.40-3.48 (m, 1H), 1.95 (ddt, 1H), 1.71-1.77 (m, 1H), 1.34-1.43 (m,2H), 1.19-1.29 (m, 1H), 1.02 (t, 3H).

Preparation 41:(1S,4S,5R,6S)-6-(fluoromethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L79)

Step 1. Synthesis of (3R,5aS,6S,6aR,6bS)-ethyl3-(4-methoxyphenyl)-5-oxohexahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazole-6-carboxylate(C100)

(Carbethoxymethyl)dimethyl-Isulfonium bromide (CAS 5187-82-6, 15 g, 64.9mmol) was dissolved in CHCl₃ (130 mL). A saturated aqueous K₂CO3solution (61 mL) was added slowly with vigorous stirring, followed byaqueous NaOH solution (50%, 5.7 mL). Stirring was continued for about 30min. The CHCl₃ layer was separated and the aqueous phase was extractedwith additional CHCl₃. The combined CHCl₃ extracts were dried overK₂CO₃, filtered and concentrated to afford a clear yellow colored liquid(9.58 g). This was dissolved in DMSO (100 mL). A solution of CAS170885-07-1 (6.17 g, 26.7 mmol) in DMSO (33 mL) was added. The mixturewas kept for 3 days at about 25° C. Ethyl acetate (500 mL) was added andthe mixture was washed with brine (3×200 mL). The combined brine washeswere extracted with EtOAc and the combined EtOAc extracts were driedover MgSO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C100. Yield: 4.0 g (47%).¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, 2H), 6.86 (d, 2H), 6.24 (s, 1H),4.19-4.24 (m, 1H), 4.13-4.19 (m, 2H), 3.96 (dd, 1H), 3.79 (s, 3H), 3.46(dd, 1H), 2.61 (dd, 1H), 2.50 (ddd, 1H), 2.24 (t, 1H), 1.27 (t, 3H).There was also obtained (3R,5aS,6R,6aR,6bS)-ethyl3-(4-methoxyphenyl)-5-oxohexahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazole-6-carboxylate(C101). Yield: 4.33 g (51%). ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, 2H),6.84 (d, 2H), 6.26 (s, 1H), 4.20 (dd, 1H), 4.08-4.15 (m, 1H), 4.08 (q,2H), 3.78 (s, 3H), 3.46 (dd, 1H), 2.37-2.45 (m, 3H), 1.10 (t, 3H).

Step 2. Synthesis of(3R,5aS,6S,6aS,6bS)-6-(hydroxymethyl)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C102)

Lithium triethylborohydride (1 M, 22.1 mL) was slowly added to asolution of compound C100 (1.80 g, 5.7 mmol) in THF (5.3 mL) at −78° C.The mixture was kept at about −78° C. for an additional about 1 h beforethe slow addition of saturated aqueous NaHCO₃ solution (4.0 mL). Themixture was allowed to warm to about 0° C., after which aqueous hydrogenperoxide solution (30%, 3.0 mL) was added dropwise to control theensuing exothermic reaction. The mixture was then kept for about 20 minat about 0° C. The THF was evaporated under educed pressure and water(10 mL) was added. The mixture was extracted with DCM and the combinedDCM extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC102. Yield: 900 mg (58%). ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, 1H), 6.86(d, 2H), 6.24 (s, 1H), 4.17 (dd, 1H), 3.92 (dd, 1H), 3.79 (s, 3H), 3.61(d, 2H), 3.42 (dd, 1H), 2.36 (br. s., 1H), 2.14 (dd, 1H), 2.00-2.06 (m,1H), 1.73-1.81 (m, 1H). There was also obtained 400 mg (25%) of thealdehyde. C108. In a similar manner, treatment of compound C101 withlithium triethylborohydride afforded C104. ¹H NMR (400 MHz, CDCl₃) δ7.29 (d, 2H), 6.87 (d, 2H), 6.27 (s, 1H), 4.24 (dd, 1H), 3.97 (dd, 1H),3.81-3.88 (m, 2H), 3.80 (s, 3H), 3.53 (dd, 1H), 2.21-2.32 (m, 2H),1.81-1.94 (m, 2H).

Step 3. Synthesis of(3R,5aS,6S,6aR,6bS)-6-(fluoromethyl)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C103)

A solution of compound C102 (200 mg 0.73 mmol) in DCM (3.6 mL) wastreated with Et₃N (1.1 mL 7.3 mmol) followed by XtalFluor-E (249 mg 1.1mmol) and triethylamine trihydrofluoride (0.24 mL 1.4 mmol) in apolyethylene vial at about 25° C. The mixture was kept for 3 days atabout 25° C. Three additional experiments were prepared similarly.Aqueous NaHCO₃ (4 mL) was added to each vial with stirring. After about20 min, the experiments were poured into aqueous NaHCO₃ and extractedwith DCM. The combined DCM extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C103. Yield: 421 mg (52%). ¹H NMR (400 MHz, CD₃CN) S 7.27(d, 2H), 6.90 (d, 2H), 6.06 (s, 1H), 4.39 (ddd, 1H), 4.20-4.34 (m, 1H),4.17 (dd, 1H), 3.97 (dd, 1H), 3.77 (s, 3H), 3.38 (dd, 1H), 2.25-2.32 (m,1H), 1.99-2.04 (m, 1H), 1.90 (dt, 1H).

Step 4. Synthesis of(1S,4S,5R,6S)-6-(fluoromethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L79)

To a stirred solution of compound C103 (421 mg, 1.5 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (15 mg,0.08 mmol). The reaction mixture was heated at about 85° C. for about1.5 h. The reaction mixture was cooled to about 25° C., concentrated,and the residue was purified by chromatography to provide the titlecompound L79. Yield: 209 mg (87%). ¹H NMR (400 MHz, CD₃OD) S 4.43 (ddd,1H), 4.31 (ddd, 1H), 3.51-3.66 (m, 3H), 2.04 (ddd, 1H), 1.93 (m, 1H),1.49 (qt, 1H).

Synthesis of(1S,4S,5R,6R)-6-(fluoromethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L78)

This compound was prepared in the same manner as compound L79,substituting compound C101 for compound C100 in Step 2. ¹H NMR (400 MHz,CDCl₃) δ 4.40 (ddd, 1H), 4.28 (ddd, 1H), 3.69 (s, 2H), 3.53-3.61 (m,1H), 1.89 (m, 2H), 1.45-1.55 (m, 1H).

Preparation 42:(1R,4S,5S)-6-(2-fluoroethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L80)

Step 1. Synthesis of (3-fluoropropyl)diphenylsulfonium tetrafluoroborate(C105)

A mixture of 1-iodo-3-fluoropropane (CAS 462-40-8, 8.80 g, 46.8 mmol),diphenyl sulfide (23.5 mL, 140 mmol) and silver(I) tetrafluoroborate(9.11 g, 46.8 mmol) in DCM (100 mL) was heated at about 38° C. for about19 h. The mixture was diluted with DCM (100 mL), filtered, and thefiltrate was concentrated to about 50 mL volume. After filtration, thefiltrate was diluted with ethyl ether (100 mL). The white precipitatewas separated from the liquid by decantation, and the precipitate waswashed with two additional portions of DCM—ethyl ether, then dried underreduced pressure to provide the title compound C105. Yield: 10.0 g(53%). ¹H NMR (400 MHz, CDCl₃) δ 7.92-8.00 (m, 4H), 7.64-7.78 (m, 6H),4.66 (dt, 2H), 4.31 (t, 2H), 2.21 (dtt, 2H).

Step 2. Synthesis of(3R,5aR,6aS,6bS)-6-(2-fluoroethyl)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C106)

A solution of compound C105 (578 mg, 1.7 mmol) in THF (15 mL) wastreated with tert-butyllithium solution (1.7 M, 1.32 mL) at about −78°C. The mixture was kept for about 30 min at about −78° C., then asolution of CAS 170885-07-1 (200 mg, 0.87 mmol) in THF (5 mL) was added.After about 3 h at about −78° C., aqueous NH₄C solution was added andthe mixture was extracted with EtOAc. The combined EtOAc extracts weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography to provide the title compound C106. Yield: 170 mg(67%). ¹H NMR (400 MHz, CD₃CN) S 7.27 (d, 2H, diastereomer 1), 7.26 (d,2H, diastereomer 2), 6.90 (d, 2H, diastereomer 1), 6.89 (d, 2H,diastereomer 2), 6.07 (s, 1H, diastereomer 1), 6.06 (s, 1H, diastereomer2), 4.60 (q, 2H, diastereomer 1), 4.48 (q, 2H, diastereomer 2), 4.24(dd, 1H, diastereomer 2), 4.20 (dd, 1H, diastereomer 1), 4.13 (dd, 1H,diastereomer 2), 3.92 (dd, 1H, diastereomer 1), 3.78 (s, 3H,diastereomer 1), 3.77 (s, 3H, diastereomer 2), 3.48 (dd, 1H,diastereomer 1), 3.34 (dd, 1H, diastereomer 2).

Step 3. Synthesis of(1R,4S,5S)-6-(2-fluoroethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L80)

To a stirred solution of compound C106 (250 mg, 0.86 mmol) in 6 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (8 mg,0.04 mmol). The reaction mixture was heated at about 90° C. for about 1h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL80. Yield: 140 mg (94%). ¹H NMR (400 MHz, CD₃CN) S 4.39-4.64 (m, 2H),3.31-3.56 (m, 2H), 3.07-3.30 (m, 1H), 2.21-2.35 (m, 2H), 0.96-1.89 (m,3H).

Preparation 43:(1S,4S,5S,6S)-4-(hydroxymethyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L81)

Step 1. Synthesis of(3R,5aS,6S,6aS,6bS)-6-(methoxymethyl)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C107)

To a stirred solution of compound C102 (400 mg, 1.46 mmol) in THF (10mL) was added freshly prepared silver(I) oxide (1.68 g, 7.27 mmol),followed by iodomethane (0.46 ml, 7.27 mmol). The mixture was heated atabout 60° C. for about 16 h. The mixture was then cooled to about 25°C., filtered and concentrated. The residue was purified bychromatography to provide the title compound C107. Yield: 180 mg (43%).¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, 2H), 6.84 (d, 2H), 4.15 (dd, 1H),3.92 (dd, 1H), 3.78 (s, 3H), 3.48 (dd, 1H), 3.40 (dd, 1H), 3.33 (s, 3H),3.21 (dd, 1H), 2.13-2.11 (m, 1H), 1.99-1.97 (m, 1H), 1.78-1.75 (m, 1H).

Step 2. Synthesis of(1S,4S,5S,6S)-4-(hydroxymethyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]-hexan-2-one(L81)

To a stirred solution of compound C107 (100 mg, 0.35 mmol) in 3.6 mL ofacetonitrile and 0.4 mL of water was added 4-toluenesulfonic acid (3 mg,0.02 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL81. Yield: 45 mg (76%). ¹H NMR (400 MHz, CDCl₃) δ 6.16 (br. s, 1H),3.68 (m, 2H), 3.56 (m, 1H), 3.48 (m, 1H), 3.33 (s, 3H), 3.17 (m, 1H),1.82 (m, 2H), 1.37 (m, 1H).

Synthesis of(1S,4S,5S,6R)-4-(hydroxymethyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L82)

This compound was prepared in the same manner as compound L81,substituting compound C104 for compound C102 in Step 1. ¹H NMR (400 MHz,CDCl₃) δ 6.42 (br. s, 1H), 3.73-3.68 (m, 1H), 3.61-3.57 (m, 3H),3.42-3.38 (m, 1H), 3.35 (s, 3H), 3.18 (br. m, 1H), 2.08-2.04 (m, 1H),1.92-1.88 (m, 1H), 1.68-1.62 (m, 1H).

Synthesis of(1S,4S,5S,6S)-6-((benzyloxy)methyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L85)

This compound was prepared in the same manner as compound L81,substituting (bromomethyl)benzene for iodomethane in Step 1. ¹H NMR (400MHz, CDCl₃) δ 7.36-7.27 (m, 5H), 5.67 (br. s, 1H), 4.49 (dd, 2H),3.67-3.54 (m 4H), 3.30-3.24 (m, 1H), 1.85-1.76 (br. m, 2H), 1.37-1.32(br. m, 1H).

Synthesis of(1S,4S,5S,6R)-6-((benzyloxy)methyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L86)

This compound was prepared in the same manner as compound L81,substituting compound C104 for compound C102, and (bromomethyl)benzenefor iodomethane, in Step 1. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.27 (m, 5H),5.96 (br. s, 1H), 4.56 (d, 1H), 4.48 (d, 1H), 3.73-3.64 (m, 2H),3.60-3.55 (m, 2H), 3.47-3.43 (m, 1H), 2.06-2.00 (m, 1H), 1.96-1.88 (m,1H), 1.72-1.64 (m, 1H).

Preparation 44:(1S,4S,5R,6S)-6-(difluoromethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L84)

Step 1. Synthesis of(3R,5aS,6S,6aS,6bS)-3-(4-methoxyphenyl)-5-oxohexahydro-1H-cyclopropa-[3,4]pyrrolo[1,2-c]oxazole-6-carbaldehyde(C108)

A solution of compound C102 (9.20 g, 33 mmol) in DCM (167 mL) and water(1 mL) was treated with Dess Martin periodinane (28.3 g, 67 mmol) andstirred at about 25° C. for about 2 h. at which time saturated aqueousNaHCO₃ solution (200 mL) was added and stirring continued for about 30min. The DCM was separated and the aqueous phase was extracted withadditional DCM. The combined DCM extracts were dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography toprovide the title compound C108. Yield: 5.50 g (60%). ¹H NMR (400 MHz,CD₃OD) S 9.40 (d, 1H), 7.32 (d, 2H), 6.93 (d, 2H), 6.17 (s, 1H), 4.29(dd, 1H), 4.12 (dd, 1H), 3.83 (s, 3H), 3.53 (dd, 1H), 2.89 (dd, 1H),2.64 (ddd, 1H), 2.59 (q, 1H).

Step 2. Synthesis of(3R,5aS,6S,6aR,6bS)-6-(difluoromethyl)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C109)

A solution of compound C108 (4.0 g, 14.6 mmol) in 1,2-dichloroethane(16.3 mL) and pyridine (24.1 mL), and a solution of DAST (7.7 mL, 58mmol) in 1,2-dichloroethane (33 mL) were prepared. A VaporTec FlowReactor fitted with 10 mL loops was used for the experiment. A 10 mLportion of the solution of compound C108 was added to first loop. A 10mL portion of the solution of DAST was added to the second loop. Bothloops were co-injected into the heating coils at a rate 0.2 mL/minute atabout 90° C. Upon exiting the reactor coil, the eluate was passedthrough a calcium carbonate plug. Upon completion of the passage, theeluate was diluted with 50 mL of DCM and washed with saturated aqueousNaHCO₃. The DCM was separated and the aqueous phase was extracted withadditional DCM. The combined DCM extracts were dried over MgSO₄,filtered and concentrated. The experiment was repeated three additionaltimes and the combined residues were purified by chromatography toprovide the title compound C109. Yield: 2.39 g (55%). ¹H NMR (400 MHz,CDCl₃) δ 7.29 (d, 2H), 6.87 (d, 2H), 6.27 (s, 1H), 5.87 (td, 1H), 4.25(dd, 1H), 3.98 (dd, 1H), 3.81 (s, 3H), 3.47 (dd, 1H), 2.42 (dd, 1H),2.30 (dd, 1H), 1.92-2.02 (m, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −117.50,−120.09.

Step 3. Synthesis of(1S,4S,5R,6S)-6-(difluoromethyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L84)

To a stirred solution of compound C109 (2.39 g, 8.0 mmol) in 87 mL ofacetonitrile and 14 mL of water was added 4-toluenesulfonic acid (80 mg,0.4 mmol). The reaction mixture was heated at about 85° C. for about 1h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL84. Yield: 1.41 g (99%). ¹H NMR (400 MHz, CDCl₃) δ 6.74 (br. s., 1H),5.83 (td, 1H), 3.67-3.76 (m, 2H), 3.55-3.63 (m, 1H), 2.03-2.14 (m, 2H),1.50-1.61 (m, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −116.67, −118.70.

Preparation 45:(1R,4S,5S,6S)-6-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L83)

Step 1. Synthesis of(3R,5aR,6S,6aS,6bS)-6-fluoro-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C110)

A solution of CAS 170885-07-1 (242 mg, 1.0 mmol) andN-[(fluoromethyl)oxidophenyl-λ⁴-sulfanylidene]-4-methylbenzenesulfonamide(CAS 1097193-08-2, 513 mg, 1.6 mmol) in THF (10 mL) was treated withlithium hexamethyldisilazide (1 M, 1.3 mL) at about −78° C. The mixturewas stirred at about −78° C. for about 10 min, then was allowed to warmto about 25° C. for about 3 h. Aqueous NH₄C solution was added and themixture was extracted twice with EtOAc. The combined EtOAc extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC110. Yield: 192 mg (70%). ¹H NMR (400 MHz, CD₃CN) δ 7.22-7.32 (m, 2H),6.85-6.95 (m, 2H), 6.05 (s, 1H), 4.88 (dd, 1H), 4.17 (dd, 1H), 3.94 (dd,1H), 3.77 (s, 3H), 3.40 (dd, 1H), 2.61 (ddd, 1H), 2.38 (dd, 1H). ¹⁹F NMR(376 MHz, CD₃CN) δ −201.68.

Step 2. Synthesis of(1R,4S,5S,6S)-6-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L83)

To a stirred solution of compound C110 (1.10 g, 4.2 mmol) in 54 mL ofacetonitrile and 6 mL of water was added 4-toluenesulfonic acid (40 mg,0.21 mmol). The reaction mixture was stirred for about 6 h, thenconcentrated. The residue was purified by chromatography to provide thetitle compound L83. Yield: 534 g (88%). ¹H NMR (400 MHz, CDCl₃) δ 5.72(br. s., 1H), 4.41-4.63 (m, 1H), 3.67-3.76 (m, 2H), 3.55-3.65 (m, 1H),2.33 (dd, 1H), 2.18 (dd, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −205.65.

Preparation 46:(1R,4S,5S,6R)-6-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L87)

Step 1. Synthesis of4-methyl-N—[(S)-(fluoromethyl)oxidophenyl-λ⁴-sulfanylidene]benzenesulfonamide(C111)

A solution of CAS 170885-07-1 (330 mg, 1.4 mmol) and4-methyl-N—[(R)-methyloxidophenyl-λ⁴-sulfanylidene]benzenesulfonamide(CAS 49620-56-6, 701 mg, 2.1 mmol) in THF (15 mL) was treated withlithium hexamethyldisilazide (1 M, 1.9 mL) at about −78° C. The mixturewas stirred at about −78° C. for about 10 min, then was allowed to warmto about 25° C. for about 3 h. Aqueous NH₄Cl solution was added and themixture was extracted twice with EtOAc. The combined EtOAc extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC111. Yield: 60 mg (16%). This was used in the next step without furthercharacterization.

Step 2. Synthesis of(1R,4S,5S,6R)-6-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L87)

To a stirred solution of compound C111 (60 mg, 0.23 mmol) in 9 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (6 mg,0.03 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL87. Yield: 25 mg (75%). This was used in the next step without furthercharacterization.

Preparation 47(1R,4S,5S,6S)-6-fluoro-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L88)

Step 1. Synthesis of(3R,5aR,6S,6aS,6bS)-6-fluoro-3-(4-methoxyphenyl)-6-methyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C112)

A solution of CAS 170885-07-1 (430 mg, 1.9 mmol) and4-methyl-N—[(R)-[(1S)-1-fluoroethyl]-oxidophenyl-λ⁴-sulfanylidene]benzenesulfonamide(CAS 1422176-84-8, 952 mg, 2.8 mmol) in THF (19 mL) was treated withlithium hexamethyldisilazide (1 M, 2.4 mL) at −78° C. The mixture wasstirred at about −78° C. for about 10 min, then was allowed to warm toabout 25° C. for about 3 h. Aqueous NH₄C solution was added and themixture was extracted twice with EtOAc. The combined EtOAc extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC112. Yield: 200 mg (39%). ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, 2H), 6.88(d, 2H), 6.24 (s, 1H), 4.25 (dd, 1H), 3.81 (s, 3H), 3.76-3.84 (m, 1H),3.50-3.57 (m, 1H), 2.39-2.54 (m, 2H), 1.56 (s, 3H). ¹⁹F NMR (376 MHz,CDCl₃) δ −157.20. There was also obtained(3R,5aR,6R,6aS,6bS)-6-fluoro-3-(4-methoxyphenyl)-6-methyltetra-hydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C113). It was used in the next step without further characterization.

Step 2. Synthesis of(1R,4S,5S,6S)-6-fluoro-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L88)

To a stirred solution of compound C112 (211 mg, 0.76 mmol) in 9 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (7 mg,0.04 mmol). The reaction mixture was heated at about 90° C. for about 2h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL88. Yield: 110 mg (91%). ¹H NMR (400 MHz, CDCl₃) 6.20 (br. s., 1H),3.69-3.78 (m, 1H), 3.54-3.68 (m, 2H), 2.68 (s, 1H), 2.32 (dd, 1H), 2.11(dd, 1H), 1.67 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −161.43.

Synthesis of(1R,4S,5S,6R)-6-fluoro-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L89)

This compound was prepared in the same manner as compound L88,substituting compound C113 for compound C112 in Step 2. It was used inthe next step without further characterization.

Preparation 48:(1R,4S,5S)-4-(hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexan-2-one(L91)

Step 1. Synthesis of(3R,5aR,6aS,6bS)-3-(4-methoxyphenyl)-5α-methyltetrahydro-1H-cyclopropa[3,4]-pyrrolo[1,2-c]oxazol-5(3H)-one(C114)

LDA (2 M, 0.31 mL) was added very slowly to a solution of(3R,5aR,6aS,6bS)-3-(4-methoxyphenyl)tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(CAS 187742-05-8, 150 mg, 0.61 mmol) and iodomethane (0.20 mL, 3 mmol)in THF (3 mL) at about −78° C. After about 1 h, an additional 0.31 mL ofLDA and 0.2 mL of iodomethane were added. The mixture was warmed toabout −20° C. over about 45 min, and allowed to warm to about 25° C. forabout 1.5 h. The mixture was poured into NaHCO₃ solution and wasextracted twice with EtOAc. The combined EtOAc extracts were dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C114. Yield: 31 mg (20%).¹H NMR (400 MHz, CD₃CN) S 7.27 (d, 2H), 6.89 (d, 2H), 6.07 (s, 1H), 4.13(dd, 1H), 3.81 (dd, 1H), 3.77 (s, 3H), 3.31 (dd, 1H), 2.06 (dd, 1H),1.30 (s, 3H), 1.08-1.18 (m, 2H).

Step 2. Synthesis of(1R,4S,5S)-4-(hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexan-2-one(L91)

To a stirred solution of compound C114 (41 mg, 0.16 mmol) in 2 mL ofacetonitrile and 0.2 mL of water was added 4-toluenesulfonic acid (2 mg,0.008 mmol). The reaction mixture was heated at about 90° C. for about45 min. The reaction mixture was cooled to about 25° C., concentrated,and the residue was purified by chromatography to provide the titlecompound L91. Yield: 21 mg (93%). ¹H NMR (400 MHz, CD₃OD) δ 3.46-3.55(m, 2H), 3.43 (q, 1H), 1.75 (dd, 1H), 1.28 (s, 3H), 0.98 (dd, 1H), 0.68(t, 1H).

Preparation 49(1S,4S,5R,6S)-1-fluoro-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L92)

Step 1. Synthesis of(3R,7aS)-6-fluoro-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C115)

To a solution of(3R,7aS)-3-(4-methoxyphenyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(CAS 170885-05-9, 16.0 g, 68.59 mmol) in THF (160 mL) was added LDA (2M, 48 mL) at about −78° C., and stirred for about 30 min. A solution ofNFSI (22.68 g, 72 mmol) in THF (80 mL) was added at about −78° C. Afterabout 30 min at about −78° C., the mixture was allowed to warm to about25° C. for about 30 min. EtOAc and water were added and the phasesseparated. The aqueous phase was extracted with EtOAc. The combinedEtOAc extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C115. Yield: 12.4 g (72%). ¹H NMR (400 MHz, CDCl₃) δ 7.36(d, 2H), 6.88 (d, 2H), 6.22 (s, 1H), 5.14 (dd, 1H), 4.40-4.29 (m, 2H),3.79 (s, 1H), 3.46 (dd, 1H), 2.62-2.51 (m 1H), 2.23-2.07 (m 1H).

Step 2. Synthesis of(3R,7aS)-6-fluoro-3-(4-methoxyphenyl)-6-(phenylselanyl)tetrahydropyrrolo-[1,2-c]oxazol-5(3H)-one(C116)

To a stirred solution of compound C115 (12.4 g, 49 mmol) in THF (130 mL)was added LDA (2 M, 35 mL) at about −78° C. and stirred for about 30 minbefore a solution of diphenyl diselenide (16.96 g, 54 mmol) in THF (70mL) was added. The mixture was kept at about −78° C. for about 30 min,then allowed to warm to about 25° C. for about 30 min. EtOAc and waterwere added and the phases separated. The aqueous phase was extractedwith EtOAc. The combined EtOAc extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C116. Yield: 13 g (65%).This was used in the next step without further characterization.

Step 3. Synthesis of(3R,7aS)-6-fluoro-3-(4-methoxyphenyl)-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one(C117)

A solution of compound C116 (13.0 g, 32 mmol) in DCM (260 mL) andpyridine (5.7 mL, 70 mmol) was treated with hydrogen peroxide (30%, 11.9mL, 106 mmol) at about 0° C. The mixture was kept at about 0° C. forabout 30 min, and allowed to warm to about 25° C. for about 2 h beforebeing diluted with DCM and water. The DCM was separated and the aqueousphase was extracted with DCM. The combined DCM extracts were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography to provide the title compound C117.Yield: 4.6 g (58%). ¹H NMR (400 MHz, CD₃CN) S 7.43 (d, 2H), 6.96 (d,2H), 6.72 (dd, 1H), 5.91 (s, 1H), 4.59 (m, 1H), 4.36 (dd, 1H), 3.80 (s,3H), 3.29-3.36 (m, 1H). ¹⁹F NMR (376 MHz, CD₃CN) δ −137.11.

Step 4. Synthesis of(3R,5aS,6S,6aR,6bS)-5α-fluoro-3-(4-methoxyphenyl)-6-methyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C118)

To a stirred suspension of ethyldiphenylsulfonium tetrafluoroborate (CAS893-69-6, 5.31 g, 17 mmol) in DME (62 mL) was added LDA (2 M, 8.0 mL, 16mmol) slowly at about −55° C. The reaction mixture was kept at about−55° C. for about 45 min, at which point it was warmed to about −35° C.and a solution of compound C117 (1.99 g, 8.0 mmol) in DME (20 mL) wasadded. The reaction mixture was maintained at about −30° C. for about1.5 h, then aqueous NaHCO₃ and EtOAc were added. The EtOAc was separatedand the aqueous phase was extracted with EtOAc. The combined EtOAcextracts were dried over MgSO₄, filtered and concentrated. The residuewas purified by chromatography to provide the title compound C118.Yield: 362 mg (16%). ¹H NMR (400 MHz, CD₃CN) S 7.28 (d, 2H), 6.90 (d,2H), 6.12 (s, 1H), 4.17 (dd, 1H), 3.78 (s, 3H), 3.66-3.75 (m, 1H), 3.45(dd, 1H), 2.33 (dd, 1H), 1.64 (d, 1H), 1.25 (dd, 3H). There was alsoobtained(3R,5aS,6R,6aR,6bS)-5α-fluoro-3-(4-methoxyphenyl)-6-methyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C119). Yield: 816 mg (37%). ¹H NMR (400 MHz, CD₃CN) δ 7.30 (d, 2H),6.92 (d, 2H), 6.15 (s, 1H), 4.20-4.24 (m, 1H), 3.78 (s, 3H), 3.57-3.62(m, 2H), 2.72 (dd, 1H), 2.13-2.23 (m, 1H), 1.15 (dd, 3H).

Step 5. Synthesis of(1S,4S,5R,6S)-1-fluoro-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]-hexan-2-one(L92)

To a stirred solution of compound C118 (400 mg, 1.4 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (14 mg,0.07 mmol). The reaction mixture was kept at about 25° C. for about 12h, then concentrated and the residue was purified by chromatography toprovide the title compound L92. Yield: 181 mg (79%). ¹H NMR (400 MHz,CDCl₃) δ 6.07 (br. s., 1H), 3.66-3.81 (m, 1H), 3.54-3.67 (m, 1H),3.36-3.50 (m, 1H), 1.77-1.87 (m, 2H), 1.29 (d, 3H).

Synthesis of(1S,4S,5R,6R)-1-fluoro-4-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(L93)

This compound was prepared in the same manner as compound L92,substituting compound C119 for compound C118 in Step 5. ¹H NMR (400 MHz,CD₃OD) S 3.63 (dd, 2H), 3.28 (dt, 1H), 2.38 (dd, 1H), 1.95-2.07 (m, 1H),1.07 (dd, 3H).

Preparation 50:(1R,4S,5S)-4-(hydroxymethyl)-5-methyl-3-azabicyclo[3.1.0]hexan-2-one(L94)

Step 1. Synthesis of(3R,7S,7aS)-3-(4-methoxyphenyl)-7-methyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C120)

A suspension cuprous bromide—dimethyl sulfide complex (2.24 g, 10.8mmol) in ether (30 mL) was cooled to about −10° C. and a solution ofmethyllithium (1.6 M, 13.5 mL) was added slowly. The mixture was thencooled to about −78° C. and TMSCl (1.36 mL, 10.8 mmol) was added slowly.After the addition was complete, the mixture was kept for about 15 minbefore(3R,7aS)-3-(4-methoxyphenyl)-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one(CAS 170885-07-1, 1.00 g, 4.3 mmol) in THF (20 mL) was added slowly. Themixture was kept an additional about 2 h at about −78° C. before beingallowed to warm to about 25° C. The mixture was kept at about 25° C. forabout 1 h before being treated with a mixture of saturated aqueous NH₄Cland ammonium hydroxide. The ethereal layer was separated and the aqueousphase was extracted twice with EtOAc. The combined extracts were driedover MgSO₄ filtered and concentrated. The residue was purified bychromatography to provide the title compound C120. Yield: 457 mg (43%).¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, 2H), 6.89 (d, 2H), 6.31 (s, 1H), 4.20(dd, 1H), 3.81 (s, 3H), 3.77 (q, 1H), 3.59 (dd, 1H), 2.61-2.72 (m, 1H),2.44-2.55 (m, 1H), 2.29-2.42 (m, 1H), 1.23 (d, 3H).

Step 2. Synthesis of(3R,7R,7aS)-3-(4-methoxyphenyl)-7-methyl-6-(phenylselanyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C121)

To a stirred solution of compound C120 (450 mg, 1.8 mmol) in THF (10 mL)was added LDA (2 M, 1.18 mL) at about −78° C. and stirred for about 30min before a solution of phenylselenenyl chloride (462 mg, 2.4 mmol) inTHF (5 mL) was added. The mixture was kept at about −78° C. for about 30min, then allowed to warm to about 25° C. for about 2 h. EtOAc and waterwere added and the phases separated. The aqueous phase was extractedwith EtOAc. The combined EtOAc extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C121. Yield: 343 mg (47%).This was used in the next step without further characterization.

Step 3. Synthesis of(3R,7aS)-3-(4-methoxyphenyl)-7-methyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one(C122)

A solution of compound C121 (343 mg, 0.85 mmol) in DCM (15 mL) andpyridine (0.15 mL) at about 0° C. was treated with 30% hydrogen peroxidesolution (0.17 mL, 2.8 mmol). The mixture was kept at about 0° C. forabout 30 min before being warmed slowly to about 25° C. After about 3 h,the mixture was diluted with DCM (10 mL) and washed with saturatedaqueous NaHCO₃ solution. The DCM extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C122. Yield: 143 mg (68%).¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, 2H), 6.91 (d, 2H), 6.18 (s, 1H), 5.82(s, 1H), 4.39-4.49 (m, 1H), 4.21 (s, 1H), 3.82 (s, 3H), 3.47 (s, 1H),2.09 (d, 3H).

Step 4. Synthesis of(3R,5aR,6aS,6bS)-3-(4-methoxyphenyl)-6α-methyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C123)

Sodium hexamethyldisilazide (1 M, 0.57 mL) was added to a suspension oftrimethylsulfoxonium iodide (128 mg, 0.57 mmol) in DMSO (2 mL) at about25° C. The mixture was kept at about 25° C. for about 30 min then heatedto about 55° C. for about 30 min. The mixture was cooled to about 25°C., then a solution of compound C122 (100 mg, 0.41 mmol) in THF (1 mL)was added. After about 18 h, aqueous NH₄Cl was added and the mixture wasextensively extracted with ethyl ether. The combined ether extracts werewashed with water, brine, dried over MgSO₄, filtered and concentrated.The residue was purified by chromatography to provide the title compoundC123. Yield: 55 mg (52%). ¹H NMR (400 MHz, CD₃CN) S 7.24-7.29 (m, 2H)6.86-6.92 (m, 2H) 6.06 (s, 1H) 4.11-4.16 (m, 1H) 3.92 (ddd, 1H) 3.77 (s,3H) 3.50 (dd, 1H) 1.72-1.77 (m, 1H) 1.30 (s, 3H) 1.19 (s, 1H) 1.17 (d,1H).

Step 5. Synthesis of(1R,4S,5S)-4-(hydroxymethyl)-5-methyl-3-azabicyclo[3.1.0]hexan-2-one(L94)

To a stirred solution of compound C123 (200 mg, 0.77 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (7 mg,0.04 mmol). The reaction mixture was heated at about 95° C. for about 1h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL94. Yield: 95 mg (87%). ¹H NMR (400 MHz, CDCl₃) δ 6.04 (br. s., 1H)3.81 (dd, 1H) 3.62-3.68 (m, 1H) 3.57-3.61 (m, 1H) 2.12 (br. s., 1H)1.62-1.68 (m, 1H) 1.30 (s, 3H) 0.99 (dd, 1H) 0.85-0.89 (m, 1H).

Synthesis of(1R,4S,5S)-5-ethyl-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L95)

This compound was prepared in the same manner as compound L94,substituting ethylmagnesium chloride for methyllithium in Step 1. It wasused in the next step without further characterization.

Preparation 51;(1S,4S,5R)-1-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L96)

Step 1. Synthesis of(3R,7R,7aS)-3-phenyl-7-vinyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C124)

A suspension cuprous bromide—dimethyl sulfide complex (10.4 g, 50 mmol)in ether (70 mL) was cooled to about −10° C. and a solution ofvinylmagnesium bromide (1 M, 100 mL) was added slowly. The mixture wasstirred at about −10° C. for about 30 min. The mixture was then cooledto about −78° C. and TMSCl (9.2 mL, 73 mmol) was added slowly. After theaddition was complete, the mixture was kept for about 15 min before(3R,7aS)-3-phenyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one (CAS134107-65-6, 6.70 g, 33 mmol) in THF (70 mL) was added slowly. Themixture was kept an additional about 4 h at about −78° C. before beingtreated with a mixture of saturated aqueous NH₄Cl and ammoniumhydroxide. The ethereal layer was separated and the aqueous phase wasextracted twice with EtOAc. The combined extracts were dried over MgSO₄filtered and concentrated. The residue was purified by chromatography toprovide the title compound C124. Yield: 5.53 g (72%). ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.47 (m, 2H), 7.31-7.40 (m, 3H), 6.39 (s, 1H), 5.88 (ddd,1H), 5.12-5.20 (m, 2H), 4.19 (dd, 1H), 3.96 (q, 1H), 3.71 (dd, 1H), 2.95(dq, 1H), 2.63-2.81 (m, 2H).

Step 2. Synthesis of(3R,7R,7aS)-6-fluoro-3-phenyl-7-vinyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C125)

A solution of LDA was generated from n-butyllithium (2.5 M, 1.1 mL) anddiisopropylamine (0.73 mL, 5.2 mmol) in THF at about 0° C. for about 1h. A solution of compound C124 (1.00 g, 4.4 mmol) in THF (40 mL) wastreated with the LDA solution at about −78° C. After about 30 min, asolution of NFSI (1.70 g, 5.2 mmol) in THF (5 mL) was added. The mixturewas allowed to warm to about 25° C. for about 16 h. Saturated aqueousNH₄Cl solution was added and the mixture was extracted with EtOAc (50mL). The EtOAc extract was washed with brine, dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography to providethe title compound C125. Yield: 441 mg (41%). ¹H NMR (400 MHz, CDCl₃) δ7.33-7.50 (m, 5H), 6.48 (s, 1H), 5.95 (ddd, 1H), 5.31-5.38 (m, 2H), 5.22(dd, 1H), 4.22-4.33 (m, 1H), 3.75-3.86 (m, 2H), 2.93-3.08 (m, 1H). ¹⁹FNMR (376 MHz, CDCl₃) δ −194.19, −198.01.

Step 3. Synthesis of(3R,7S,7aS)-6-fluoro-7-(hydroxymethyl)-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C126)

A stream of ozonized oxygen was bubbled through a solution of compoundC125 (440 mg, 1.8 mmol) in DCM (6 mL) and MeOH (2 mL) at about −78° C.After a blue color persisted in the mixture, the mixture was treatedwith dimethyl sulfide (3 mL). NaBH₄ (202 mg, 5.3 mmol) was added and themixture was stirred at about −78° C. for about 30 min before beingallowed to warm to about 0° C. for about 30 min. The mixture was treatedwith saturated aqueous NH₄Cl solution and extracted with EtOAc. TheEtOAc extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C126. Yield: 207 mg (46%). ¹H NMR (400 MHz, CDCl₃) δ7.31-7.50 (m, 5H), 6.44 (s, 1H), 5.31 (dd, 1H), 4.36 (dd, 1H), 4.04 (dt,1H), 3.87-3.97 (m, 2H), 3.76 (dd, 1H), 2.49-2.69 (m, 1H), 1.69 (t, 1H).¹⁹F NMR (376 MHz, CDCl₃) δ −193.64.

Step 4. Synthesis of(3R,7R,7aS)-7-(bromomethyl)-6-fluoro-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C127)

A solution of compound C126 (202 mg, 0.8 mL) in DCM was treated withpyridine (0.13 mL, 1.6 mmol) and carbon tetrabromide (323 mg, 1.0 mmol).Triphenylphosphine (258 mg, 1.0 mmol) was slowly added to the mixture.The mixture was kept about 2 h at about 25° C., then saturated aqueousNaHCO₃ was added and the mixture was extracted with EtOAc. The combinedEtOAc extracts were washed with water, brine, dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography to providethe title compound C127. Yield: 185 mg (73%). ¹H NMR (400 MHz, CDCl₃) δ7.34-7.47 (m, 5H), 6.45 (s, 1H), 5.21 (dd, 1H), 4.41-4.49 (m, 1H),3.82-3.89 (m, 2H), 3.76-3.81 (m, 1H), 3.56 (dd, 1H), 2.74-2.88 (m, 1H).¹⁹F NMR (376 MHz, CDCl₃) δ −193.19.

Step 5. Synthesis of(3R,5aS,6aR,6bS)-5α-fluoro-3-phenyltetrahydro-1H-cyclopropa[3,4]pyrrolo-[1,2-c]oxazol-5(3H)-one(C128)

A solution of compound C127 (185 mg, 0.59 mmol) in THF (10 mL) wastreated with lithium hexamethyldisilazide (1 M, 0.62 mL) at about −78°C. After about 15 min at about −78° C., the mixture was allowed to warmto about 0° C. for about 30 min, then an additional portion of lithiumhexamethyldisilazide (1 M, 0.31 mL) was added. After approximatelyanother 30 min at about 0° C., The mixture was treated with withsaturated aqueous NH₄Cl solution and extracted with EtOAc. The combinedEtOAc extracts were washed with water, brine, dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography to providethe title compound C128. Yield: 110 mg (80%). ¹H NMR (400 MHz, CDCl₃) δ7.29-7.44 (m, 5H), 6.40 (s, 1H), 4.26 (dd, 1H), 3.61-3.69 (m, 1H),3.53-3.60 (m, 1H), 2.60 (td, 1H), 1.90 (ddd, 1H), 1.44 (dt, 1H). ¹⁹F NMR(376 MHz, CDCl₃) δ −208.58.

Step 6. Synthesis of(1S,4S,5R)-1-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L96)

To a stirred solution of compound C128 (110 mg, 0.47 mmol) in 18 mL ofacetonitrile and 2 mL of water was added 4-toluenesulfonic acid (5 mg,0.02 mmol). The reaction mixture was kept at about 25° C. for about 6 h,then heated at about 60° C. for about 6 h. The reaction mixture wascooled to about 25° C., concentrated, and the residue was purified bychromatography to provide the title compound L96. Yield 53 mg (77%). Itwas used in the next step without further characterization.

Preparation 52:(1R,4S,5S)-4-(hydroxymethyl)-3-azabicyclo[3.2.0]heptan-2-one (L97)

Step 1. Synthesis of (1S,2S,5R)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-4-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate(C129)

A solution of (S)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate(CAS 81658-27-7, 1.00 g, 3.1 mmol) in acetone (330 mL) was saturatedwith ethylene gas and irradiated with ultraviolet light at about −20° C.for about 6 h. A steady flow of ethylene gas was maintained throughoutthe irradiation. The mixture was then concentrated and the residue waspurified by chromatography to provide the title compound C129. Yield:250 mg (23%). ¹H NMR (400 MHz, CDCl₃) δ 3.89 (s, 1H), 3.81 (dd, 1H),3.59 (d, 1H), 3.03 (t, 1H), 2.88 (q, 1H), 2.49-2.44 (m, 1H), 2.29-2.25(m, 1H), 2.11-1.99 (m, 2H), 1.54 (s, 9H), 0.84 (s, 9H), 0.06 (m, 6H).

Step 2. Synthesis of (1S,2S,5R)-tert-butyl2-(hydroxymethyl)-4-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate (C130)

A solution of compound C129 (568 mg, 1.6 mmol) in THF (8 mL) was treatedwith a solution off tetrabutylammonium fluoride (1 M, 3.2 mL) at about25° C. After about about 4 h, the mixture was poured into water andextracted with EtOAc. The combined EtOAc extracts were dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography toprovide the title compound C130. Yield: 357 mg (93%). ¹H NMR (400 MHz,CDCl₃) δ 6.66 (br. s., 1H), 3.90-4.01 (m, 1H), 3.79-3.86 (m, 1H), 3.61(t, 1H), 2.91-2.99 (m, 1H), 2.78-2.88 (m, 1H), 2.41-2.52 (m, 1H),2.30-2.41 (m, 1H), 2.01-2.16 (m, 2H), 1.46 (s, 9H).

Step 3. Synthesis of(1R,4S,5S)-4-(hydroxymethyl)-3-azabicyclo[3.2.0]heptan-2-one (L97)

Compound C130 (357 mg, 1.5 mmol) was dissolved in DCM (1 mL) at about25° C. A mixture of DCM (1 mL) and TFA (1 mL) was added and the mixturewas kept at about 25° C. for about 2 h. It was then concentrated todryness to provide the title compound L97. Yield: 211 mg (100%). ¹H NMR(400 MHz, CDCl₃) δ 5.55 (br. s., 2H), 4.34 (dd, 1H), 4.17 (dd, 1H), 3.82(t, 1H), 3.02-3.18 (m, 1H), 2.82-2.99 (m, 1H), 2.48-2.64 (m, 1H),2.36-2.48 (m, 1H), 2.02-2.26 (m, 2H).

Preparation 53:(1S,4S,5R)-1-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.2.0]heptan-2-one(L98)

Step 1. Synthesis of(3R,5aS,7aR,7bS)-5α-fluoro-3-(4-methoxyphenyl)hexahydrocyclobuta[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C131)

A solution of compound C117 (300 mg, 1.2 mmol) in acetone (450 mL) wassaturated with ethylene gas and irradiated with ultraviolet light atabout −20° C. for about 6 h. A steady flow of ethylene gas wasmaintained throughout the irradiation. The mixture was then concentratedand the residue was purified by chromatography to provide the titlecompound C131. Yield: 170 mg (51%). ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d,2H), 6.90 (d, 2H), 6.37 (s, 1H), 4.21 (dd, 1H), 3.81 (s, 3H), 3.78-3.74(m, 1H), 3.32 (dd, 1H), 3.06-3.01 (m, 1H), 2.65-2.56 (m, 2H), 2.49-2.42(m, 1H), 1.67-1.62 (m, 1H).

Step 2. Synthesis of(1S,4S,5R)-1-fluoro-4-(hydroxymethyl)-3-azabicyclo[3.2.0]heptan-2-one(L98)

To a stirred solution of compound C131 (200 mg, 0.72 mmol) in 9 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (7 mg,0.04 mmol). The reaction mixture was heated at about 70° C. for about 1h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL98. Yield: 115 (100%). ¹H NMR (400 MHz, CDCl₃) δ 7.84 (br. s., 1H),3.55-3.71 (m, 2H), 3.39-3.55 (m, 2H), 2.81-3.00 (m, 1H), 2.41-2.60 (m,2H), 2.18-2.34 (m, 1H), 1.36-1.53 (m, 1H).

Preparation 54:(±)-(1S,5S)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one (L100)

Step 1. Synthesis of tert-butyl1-((benzoyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (C132)

A solution of tert-butyl1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (CAS161152-76-7, 427 mg, 2 mmol) in DCM (6.4 mL) was treated with benzoicacid (368 mg, 3 mmol), EDCl hydrochloride (581 mg, 3 mmol), and DMAP (49mg, 0.4 mmol), and heated to about 40° C. for about 12 h. The mixturewas cooled to about 25° C., diluted with DCM, washed with 1 M HCl and10% aqueous Na₂CO₃. The DCM solution was concentrated, and the residuewas purified by chromatography to provide the title compound C132, whichwas used in the next step without further characterization. Yield: 0.57g (90%).

Step 2. Synthesis of tert-butyl1-((benzoyloxy)methyl)-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate(C133)

A solution of compound C132 (0.57 g, 1.8 mmol) in EtOAc (20 mL) wastreated with a solution of sodium periodate (1.5 g, 7.2 mmol) in water(20 mL) and ruthenium trichloride (21 mg (50%), 0.054 mmol). The mixturewas stirred at about 20° C. for about 6 h, then treated with 2-propanol(20 mL) and stirred for about 0.5 h. It was then diluted with water andextracted twice with EtOAc. The combined EtOAc extracts extracts weredried over Na₂SO₄ filtered and concentrated. The residue was purified bychromatography to provide the title compound C133, which was used in thenext step without further characterization. Yield: 0.40 g (60%).

Step 3. Synthesis of (4-oxo-3-azabicyclo[3.1.0]hexan-1-yl)methylbenzoate (C134)

A solution of compound C133 (0.40 g, 0.5 mmol) in DCM (2 mL) was treatedwith TFA (0.5 mL) and stirred at about 25° C. for about 15 minutes. Themixture was concentrated and the residue was redissolved in toluene andagain concentrated to provide the title compound C134, which was used inthe next step without further characterization.

Step 4. Synthesis of (5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one(L00)

Compound C134 (presumed 0.4 mmol) in THF (2 mL) was treated with NaOH(0.3 mL of a 2 M aqueous solution, 0.6 mmol) and stirred at about 25° C.for about 1 h. This solution of compound L100 was used in the next stepwithout further characterization.

Preparation 55: (±)-3-(hydroxymethyl)octahydro-1H-isoindol-1-one (L101)

Step 1. Synthesis of (±)-3-(hydroxymethyl)octahydro-1H-isoindol-1-one(L101)

Ethyl 3-oxooctahydro-1H-isoindole-1-carboxylate (CAS 84385-29-5, 400 mg,1.9 mmol) was dissolved in THF (9.5 mL) to which lithium borohydride (59mg, 2.65 mmol) was added. The reaction was stirred at about 25° C.overnight. The mixture was cooled to about 0° C. and 2 M HCl was addeddropwise until gas evolution ceased. The solution was neutralized withK₂CO3 and filtered. The filtrate was concentrated The residue waspurified by chromatography to provide the title compound L101. Yield:0.26 g (81%). ¹H NMR (400 MHz, dmso-d₆) δ 4.63 (t, 1H), 3.42-3.50 (m,1H), 3.38-3.42 (m, 2H), 2.35-2.40 (m, 1H), 2.23-2.30 (m, 1H), 1.90-1.98(m, 1H), 1.40-1.63 (m, 3H), 1.27-1.40 (m, 1H), 0.84-1.11 (m, 3H).

Preparation 56: (S)-5-(hydroxymethyl)-5-methylpyrrolidin-2-one (L102)

Step 1. Synthesis of (S)-methyl 2-methyl-5-oxopyrrolidine-2-carboxylate(C135)

A solution (S)-1-tert-butyl 2-methyl2-methyl-5-oxopyrrolidine-1,2-dicarboxylate (CAS 1109790-91-1, 1.2 g,4.7 mmol) in DCM was treated with TFA (0.36 mL, 4.7 mmol) for about 2 hat about 25° C. The mixture was concentrated to provide the titlecompound C135. Yield: 1.2 g (100%). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (br.s., 1H), 3.80 (s, 3H), 2.48-2.66 (m, 3H), 2.02-2.15 (m, 1H), 1.58 (s,3H).

Step 2. Synthesis of (S)-5-(hydroxymethyl)-5-methylpyrrolidin-2-one(L102)

A solution of compound C135 (1.2 g, 4.7 mmol) in THF (76 mL) was treatedwith lithium borohydride (218 mg, 9.9 mmol). The reaction was allowed toproceed overnight, after which the solution was cooled to about 0° C.and 2 M HCl was added dropwise until gas evolution ceased. The solutionwas neutralized with K₂CO3 and filtered. The filtrate was concentrated.The residue was purified by chromatography to provide the title compoundC136 an oil which crystallized. This was triturated with ether andfiltered to provide the title compound L102. Yield: 0.30 g (49%). ¹H NMR(400 MHz, dmso-d₆) δ 7.43 (br. s., 1H), 4.83-4.87 (m, 1H), 3.16-3.24 (m,2H), 2.06-2.21 (m, 2H), 1.96 (ddd, 1H), 1.59 (ddd, 1H), 1.09 (s, 3H).

Preparation 57: 5-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidin-2-one(L104)

Step 1. Synthesis of Diethyl2-((diphenylmethylene)amino)-3-(trifluoromethyl)pentanedioate (C136)

A mixture of ethyl 2-((diphenylmethylene)amino)acetate (CAS 69555-14-2,1.9 g, 7 mmol), benzyltriethyl NH₄Cl (0.3 g, 1.3 mmol), 10% aqueous NaOH(10 mL) and DCM (10 mL) was stirred at about 0° C. for about 15 min.Following the addition of (E)-ethyl 4,4,4-trifluorobut-2-enoate (CAS25597-16-4, 1 mL, 7 mmol) the mixture was stirred vigorously for about90 min at about 0° C. The DCM was separated and the aqueous phase wasextracted with DCM. The combined DCM extracts were washed with brine,dried over MgSO₄, filtered and concentrated to provide the titlecompound C136. Yield: 2.6 g (85%). ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.67(m, 2H), 7.43-7.50 (m, 4H), 7.31-7.38 (m, 2H), 7.14-7.20 (m, 2H), 4.43(d, 1H), 4.13-4.25 (overlapping q, 4H), 3.62-3.74 (m, 1H), 3.12 (dd,1H), 2.81 (dd, 1H), 1.27 (overlapping t, 6H).

Step 2. Synthesis of Ethyl5-oxo-3-(trifluoromethyl)pyrrolidine-2-carboxylate (C137)

A mixture of compound C136 (2.6 g, 6.0 mmol), 10% aqueous citric acid(24 mL, 212 mmol) and THF (17 mL) was stirred at about 25° C. for 2days. The reaction was extracted with EtOAc and the combined EtOAcextracts were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C137. Yield: 1.1 g (85%). ¹H NMR (400 MHz, CDCl₃) δ 6.72(br. s., 1H), 4.28 (q, 2H), 3.40 (m, 1H), 2.70 (dd, 1H), 2.52 (dd, 1H),1.33 (t, 3H).

Step 3. Synthesis of5-(Hydroxymethyl)-4-(trifluoromethyl)pyrrolidin-2-one (L104)

To a solution of compound C137 (1.1 g, 5.1 mmol) in THF (25 mL) wasadded lithium borohydride (0.16 g, 7.1 mmol). The mixture was stirred atabout 25° C. overnight. The mixture was cooled to about 0° C. and 2 MHCl was added until gas evolution ceased. The mixture was neutralizedwith K₂CO3 and filtered. The filtrate was concentrated and the residuewas purified by chromatography to provide the title compound L104.Yield: 0.44 g (47%). ¹H NMR (400 MHz, dmso-d₆) δ 7.92 (br. s., 1H,diastereomer 1), 6.89 (d, 1H, diastereomer 2), 5.35 (m, 1H, diastereomer2), 5.07 (t, 1H, diastereomer 1), 3.84 (m, 1H, diastereomer 2), 3.58 (m,1H, diastereomer 1), 3.30-3.46 (m, 3H, mixture of 1H diastereomer 1 and2H diastereomer 2), 3.12 (m, 1H, diastereomer 1), 2.74 (dd, 1H,diastereomer 2), 2.59 (dd, 1H, diastereomer 1), 2.42 (dd, 1H,diastereomer 2), 2.17 (dd, 1H, diastereomer 1).

Preparation 58:(±)-((1R,6S)-3-benzyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol (L105)

Step 1. Synthesis of(±)-((1R,6S)-3-benzyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol (L105)

To obtain the desired target material,(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)methanol (CAS 244267-39-8, 545mg, 2.7 mmol)) was cyclopropanated as described in Tetrahedron 2003, 59,6363 to provide the title compound L105. Yield: 252 mg (43%). ¹H NMR(400 MHz, dmso-d₆) δ 7.13-7.41 (m, 5H), 4.42 (t, 1H), 3.32-3.49 (m, 2H),3.28 (dd, 1H), 3.08 (dd, 1H), 2.74 (d, 1H), 2.21-2.39 (m, 2H), 1.77-1.98(m, 2H), 1.49-1.70 (m, 1H), 0.69-0.85 (m, 1H), 0.39-0.53 (m, 2H).

Preparation 59: (S)-4-(hydroxymethyl)-1-methylimidazolidin-2-one (L106)

Step 1. Synthesis of (S)-1-Benzyl 5-methyl2-oxoimidazolidine-1,5-dicarboxylate (C138)

To a suspension of(S)-3-((benzyloxy)carbonyl)-2-oxoimidazolidine-4-carboxylic acid (CAS59760-01-9, 3.0 g, 11.4 mmol) in MeOH (40 mL) was added thionyl chloride(0.4 mL, 5.7 mmol) slowly at about 25° C. The mixture was stirred atabout 25° C. overnight before the volatiles where removed under reducedpressure. The residue was dissolved in DCM and the DCM was washed withsaturated aqueous NaHCO₃. The DCM was dried over MgSO₄, filtered andconcentrated to provide the title compound C138. Yield: 2.9 g (93%). ¹HNMR (400 MHz, dmso-d₆) δ 7.26-7.45 (m, 5H), 5.19 (q, 2H), 4.78 (dd, Hz,1H), 3.66 (s, 3H), 3.63-3.71 (m, 1H), 3.37 (dd, 1H), 2.71 (s, 3H).

Step 2. Synthesis of (S)-1-Benzyl 5-methyl3-methyl-2-oxoimidazolidine-1,5-dicarboxylate (C139)

To a solution of compound C138 (0.96 g, 3.5 mmol) in DME (17 mL) wasadded K₂CO3 (0.96 g, 6.9 mmol) followed by iodomethane (0.87 mL, 13.9mmol). The mixture was heated at about 50° C. for about 19 h. Themixture was then allowed to cool to about 25° C. and diluted with water.The layers were separated and the aqueous phase was extracted threetimes with EtOAc. The combined DME and EtOAc extracts were washed withhalf—saturated aqueous NH₄Cl, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C139. Yield: 0.75 g (74%). ¹H NMR (400 MHz, dmso-d₆) δ7.31-7.44 (m, 5H), 5.19 (dd, 2H), 4.78 (dd, 1H), 3.67-3.74 (m, 1H), 3.37(dd, 1H), 3.31 (s, 2H), 2.71 (s, 3H).

Step 3. Synthesis of (S)-Benzyl5-(hydroxymethyl)-3-methyl-2-oxoimidazolidine-1-carboxylate (C140)

NaBH₄ (119 mg, 3.1 mmol) was added slowly to solution of compound C139(0.75 g, 2.6 mmol) in EtOH (7 mL) at about 0° C. The mixture was stirredat about 0° C. for about 2.5 h, at which time after which an additional119 mg of NaBH₄ was added. Stirring was continued at about 0° C. forapproximately an additional 1.5 h. Hydrochloric acid (10%) was addeddropwise to the cooled mixture until the evolution of gas ceased. Themixture was concentrated under reduced pressure and the residue wastaken up in EtOAc. The EtOAc extract was washed with saturated aqueousNaHCO₃, water, brine, dried over Na₂SO₄, filtered and concentrated toprovide the title compound C140. Yield: 200 mg (30%). ¹H NMR (400 MHz,dmso-d₆) δ 7.24-7.49 (m, 5H), 5.10-5.28 (m, 2H), 5.02 (t, 1H), 4.04-4.19(m, 1H), 3.42-3.60 (m, 2H), 3.25 (dd, 1H), 2.71 (s, 3H).

Step 4. Synthesis of (S)-4-(Hydroxymethyl)-1-methylimidazolidin-2-one

To a solution of compound C140 (200 mg, 0.74 mmol) in MeOH (19 mL) wasadded palladium on carbon (25 mg) and the mixture was stirred under ahydrogen atmosphere (1 atm) for about 6 h. The mixture was filtered andthe filtrate was concentrated. The residue was purified bychromatography to provide the title compound L106. Yield: 61 mg (64%).¹H NMR (400 MHz, dmso-d₆) δ 3.46-3.55 (m, 1H), 3.31-3.38 (m, 2H),3.24-3.31 (m, 1H), 3.05 (dd, 1H), 2.59 (s, 3H).

Preparation 60: 1-benzyl-6-hydroxy-1-azaspiro[4.4]nonan-2-one (L107)

Step 1. Synthesis of 1-benzyl-1H-pyrrol-2(5H)-one (C141)

A mixture of 2,5-dimethoxy-2,5-dihydrofuran (12.2 mL, 100 mmol),N-benzylamine (10.9 mL, 100 mmol), conc. HCl (12.5 mL, 150 mmol) and H₂O(400 mL) was stirred for about 5 h at about 25° C. The mixture wasneutralized with solid NaHCO₃ and extracted with EtOAc. The EtOAcextracts were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography to provide the title compound C141.Yield: 5.0 g (29%). ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.38 (m, 5H),6.33-6.36 (m, 1H), 5.29-5.32 (m, 1H), 4.65 (s, 2H), 3.14-3.15 (m, 2H).

Step 2. Synthesis of1-benzyl-2-((tert-butyldimethylsilyl)oxy)-1H-pyrrole (C142)

To a solution of compound C141 (2.0 g, 12 mmol) and Et₃N (3.3 mL, 23mmol) in anhydrous DCM (20 mL) was added t-butyldimethylsilyl triflate(2.4 mL, 12 mmol) at about 25° C. After about 5 h the reaction mixturewas diluted with EtOAc and H₂O. The aqueous phase was separated andextracted with EtOAc. The combined EtOAc extracts were washed withsaturated aqueous NaHCO₃ and concentrated. The residue was purified bychromatography to provide the title compound C142. Yield: 2.0 g (61%).¹H NMR (400 MHz, CDCl₃) δ 7.10-7.15 (m, 4H), 6.90-6.93 (m, 1H),6.03-6.04 (m, 1H), 5.78-5.80 (m, 1H), 5.07-5.09 (m, 1H), 4.76 (s, 2H),0.073 (s, 9H), 0.00 (s, 6H).

Step 3. Synthesis of1-benzyl-5-(1-hydroxycyclobutyl)-1H-pyrrol-2(5H)-one (C143)

To a solution of compound C142 (500 mg, 1.7 mmol) in DCM (12 mL) at 25°C. was added 3A molecular sieves and cyclobutanone (0.21 mL, 2.8 mmol).The resulting mixture was stirred for about 15 min at about 25° C. andwas then cooled to about −78° C. BF₃-Et₂O (0.32 mL, 370 mg, 2.6 mmol)was added dropwise. The mixture was stirred at about −78° C. for about 2h then warmed to about 0° C. and quenched with H₂O. The DCM wasseparated, washed with saturated aqueous NaHCO₃, and the aqueous phasewas extracted with DCM. The DCM extracts were washed with satd. NaHCO₃,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography to provide the title compound C143. Yield: 300 mg(71%). ¹H NMR (300 MHz, CDCl₃) δ 7.09-7.24 (m, 5H), 6.90-6.92 (m, 1H),6.23-6.25 (m, 1H), 5.00 (d, 1H), 4.27 (d, 1H), 4.05-4.06 (m, 1H),2.21-2.23 (m, 1H), 1.95-2.04 (m, 2H), 1.82-1.86 (m, 2H), 1.81 (s, 1H),1.42-1.49 (m, 1H).

Step 4. Synthesis of 1-benzyl-1-azaspiro[4.4]nonane-2,6-dione (C144)

To a solution of compound C143 (300 mg, 1.2 mmol) in DCM (20 mL) at 0°C. was added concentrated HCl (0.2 mL, 2.2 mmol). The mixture wasstirred at about 0° C. for about 5 h and concentrated to afford compoundC144 which was used without purification. ¹H NMR (400 MHz, CDCl₃) δ7.06-7.30 (m, 5H), 4.75 (d, 1H), 3.90 (d, 1H), 2.37-2.59 (m, 2H),2.21-2.37 (m, 1H), 1.99-2.10 (m, 1H), 1.83-1.99 (m, 3H), 1.58-1.83 (m,3H).

Step 5. Synthesis of 1-benzyl-6-hydroxy-1-azaspiro[4.4]nonan-2-one(L107)

NaBH₄ (38 mg, 0.93 mmol) was added to a solution of compound C144 (150mg, 0.62 mmol) in MeOH (4 mL). The mixture was stirred at about 25° C.for about 20 min before being diluted with H₂O and extracted with EtOAc.The combined EtOAc extracts were washed with water, brine, dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound L107 as a mixture ofdiastereomers. Yield: 105 mg (70%). It was used in the next step withoutfurther characterization.

Preparation 61: (S)-4-(hydroxymethyl)imidazolidin-2-one (L108)

Step 1. Synthesis of methyl (4S)-2-oxoimidazolidine-4-carboxylate (C145)

A suspension of 1-benzyl 5-methyl(5S)-2-oxoimidazolidine-1,5-dicarboxylate (CAS 168399-08-4, 325 mg, 1.2mmol) and 10% Pd/C (33 mg) in MeOH (4.7 mL) was shaken under a hydrogenatmosphere at about 25° C. for about 5.5 h. The mixture was filtered andconcentrated to afford the title compound C145. Yield: 163 mg (97%). ¹HNMR (400 MHz, dmso-d₆) δ 6.73 (s, 1H), 6.34 (s, 1H), 4.25 (ddd, 1H),3.52-3.65 (m, 2H), 3.32 (2, 3H).

Step 2. Synthesis of (4S)-4-(hydroxymethyl)imidazolidin-2-one (L108)

Sodium borohydride (56 mg, 1.4 mmol) was added to a solution of compoundC145 (160 mg, 1.1 mmol) at about 0° C. The mixture was stirred at about0° C. for about 3h, and then 10% HCl solution was added dropwise untilgas evolution ceased. The mixture was concentrated and the residue wasdiluted with EtOAc. The EtOAc was washed with saturated aqueous NaHCO₃,brine, dried over Na₂SO₄, filtered and concentrated to provide the titlecompound L108. Yield: 360 mg (a mixture of desired product and salts).This was used in the next step without purification. ¹H NMR (400 MHz,dmso-d₆) δ 3.53-3.61 (m, 1H), 3.30-3.36 (m, 2H), 3.23-3.30 (m, 1H), 3.04(dd, 1H).

Preparation 62:(3S,3aR,6aS)-5-benzyl-3-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one(L109)

Step 1. Synthesis of(5aS,8aR,8bS)-7-benzyl-3,3-dimethylhexahydro-1H-pyrrolo[3′,4′:3,4]-pyrrolo[1,2-c]oxazol-5(3H)-one(C146)

A solution of compound P20 (100 mg, 0.65 mmol) in DCM (5 mL) andN-(methoxymethyl)-N-[(trimethylsilyl)methyl]-benzenemethanamine (CAS93102-05-7, 232 mg, 0.98 mmol) was treated with TFA (0.01 mL, 0.13 mmol)at 0° C. The mixture was kept at about 25° C. for about 16 h, thenheated at about 40° C. for about 4 h, before an additional 232 mg of CAS93102-05-7 was added. Heating was continued for about 16 h. The reactionmixture was cooled to about 25° C., neutralized with Et₃N (18 μL, 0.13mmol), and concentrated. The residue was purified by chromatography toprovide the title compound C146. Yield: 110 mg (59%). ¹H NMR (400 MHz,dmso-d₆) δ 7.16-7.41 (m, 5H), 3.98 (dd, 1H), 3.78-3.87 (m, 1H),3.59-3.68 (m, 1H), 3.48-3.58 (m, 1H), 3.35 (dd, 1H), 3.10 (t, 1H), 2.95(d, 1H), 2.79 (d, 1H), 2.56-2.66 (m, 1H), 2.24 (t, 1H), 2.18 (dd, 1H),1.53 (s, 3H), 1.33 (s, 3H).

Step 2. Synthesis of(3S,3aR,6aS)-5-benzyl-3-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one(L109)

To a stirred solution of compound C5146 (110 mg, 0.38 mmol) in 6 mL ofacetonitrile and 0.6 mL of water was added TFA (36 μL, 0.46 mmol). Thereaction mixture was heated at about 60° C. for about 2 h. The reactionmixture was cooled to about 25° C., concentrated, and the residue waspurified by chromatography to provide the title compound L109. Yield: 60mg (64%). ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.37 (m, 5H), 3.61 (s, 2H),3.46-3.55 (m, 2H), 3.39-3.45 (m, 1H), 2.92-3.02 (m, 2H), 2.66-2.78 (m,2H), 2.57 (dd, 1H), 2.45-2.53 (m, 1H).

Preparation 63:2-((5S)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl)acetonitrile (L110)

Step 1: Synthesis of (5S)-tert-butyl5-(((tert-butoxycarbonyl)oxy)methyl)-3-(cyanomethyl)-2-oxopyrrolidine-1-carboxylate(C147)

LDA solution (2 M, 2.4 mL) was added to a solution of (S)-tert-butyl2-(((tert-butoxycarbonyl)-oxy)methyl)-5-oxopyrrolidine-1-carboxylate(CAS 360782-62-3, 1.0 g, 3.2 mmol) in THF (20 mL) at about −78° C. Afterabout 30 min, bromoacetonitrile (0.22 mL, 3.2 mmol) was added. Themixture was stirred at about −78° C. for about 20 min, and thensaturated aqueous NaHCO₃ (2 mL) was added. The mixture was diluted withH₂O and extracted with EtOAc. The combined EtOAc extracts were washedwith H₂O, brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography to provide the title compoundC147. Yield: 0.86 g (77%). ¹H NMR (400 MHz, CDCl₃) δ 4.50 (dd, 1H),4.36-4.44 (m, 1H), 4.10-4.19 (m, 1H), 3.08-3.22 (m, 1H), 2.88 (dd, 1H),2.60 (dd, 1H), 2.41 (dd, 1H), 2.06-2.20 (m, 1H), 1.53-1.62 (m, 18H).

Step 2. Synthesis of2-((5S)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl)acetonitrile (L110)

Concentrated HCl (2 mL) was added to a solution of compound C147 (500mg, 1.4 mmol) in MeOH (5 mL) and DCM (5 mL). The mixture was stirred atabout 25° C. overnight, then concentrated provide the title compoundL110. ¹H NMR (400 MHz, CD₃OD) δ 3.76-3.67 (m, 1 H), 3.56-3.48 (m, 2H),2.90-2.87 (m, 1H), 2.73-2.65 (m, 2H), 2.27-2.24 (m, 1H), 2.12-2.05 (m,1H).

Preparation 64: (1S,3aS,6aR)-di-tert-butyl1-(hydroxymethyl)-3-oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate(L111)

Step 1. Synthesis of (1S,3aS,6aR)-tert-butyl5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(C148)

A solution of (S)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate(CAS 81658-27-7, 3.0 g, 9.2 mmol) andN-(methoxymethyl)-N-[(trimethylsilyl)methyl]-benzenemethanamine (CAS93102-05-7, 3.27 g, 13.8) in DCM (80 mL) was treated with TFA (208 mg,1.84 mmol) at about 25° C. and kept for about 18 h. Triethylamine (0.26mL, 1.84 mmol) was added and mixture was concentrated. The residue waspurified by chromatography to provide the title compound C148. Yield:2.6 g (61%). ¹H NMR (400 MHz, dmso-d₆) δ 7.27-7.34 (m, 2H), 7.19-7.27(m, 3H), 3.87-3.91 (m, 1H), 3.84 (dd, 1H), 3.65 (d, 1H), 3.53 (s, 2H),2.90-2.97 (m, 1H), 2.82-2.89 (m, 1H), 2.65-2.73 (m, 2H), 2.54-2.63 (m,2H), 1.45 (s, 9H), 0.82 (s, 9H), 0.01 (s, 3H), −0.02 (s, 3H)

Step 2: Synthesis of (1S,3aS,6aR)-di-tert-butyl1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate(C149)

To a solution of compound C148 (2.2 g, 4.8 mmol) and di-t-butyldicarbonate (3.1 g, 14.4 mmol) in MeOH (150 mL) was added palladium oncarbon (200 mg) and the mixture was stirred under a hydrogen atmosphere(1 atm) for about 18 h. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by chromatography to provide thetitle compound C149. Yield: 1.12 g (49%). ¹H NMR (400 MHz, CD₃OD) δ3.99-4.10 (m, 2H), 3.68-3.88 (m, 4H), 3.45-3.55 (m, 1H), 3.11 (dd, 1H),2.87-2.99 (m, 1H), 1.54 (s, 9H), 1.45 (s, 9H), 0.89 (s, 9H), 0.08 (s,3H), 0.06 (s, 3H).

Step 3. Synthesis of (1S,3aS,6aR)-di-tert-butyl1-(hydroxymethyl)-3-oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate(L111)

A solution of compound C149 (1.22 g, 2.6 mmol) in THF (100 mL) wastreated with tetrabutylammonium fluoride (1 M, 3.9 mL) at about 25° C.After about 2 h, the mixture was concentrated. The residue was purifiedby chromatography to provide the title compound L111. Yield: 600 mg(65%). ¹H NMR (400 MHz, CD₃OD) δ 4.18 (dd, 1H), 4.05 (dd, 1H), 3.69-3.82(m, 2H), 3.56-3.69 (m, 1H), 3.47 (dd, 1H), 3.21 (dd, 1H), 3.08-3.17 (m,1H), 2.87-2.99 (m, 1H), 1.46 (s, 9H), 1.46 (s, 9H)

Preparation 65: (4R,5S)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(L112)

Step 1. Synthesis of (4R,5S)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(L112)

To a mixture of (4S,5S)-methyl 5-methyl-2-oxooxazolidine-4-carboxylate(CAS 182267-22-7, 165 mg, 1.0 mmol) in EtOH (6 mL) at about 0° C. wasadded NaBH₄ (43 mg, 1.1 mmol). After gas evolution ceased, the mixturewas stirred at about 25° C. for about 4 h. The mixture was re-cooled toabout 0° C. and additional NaBH₄ (35 mg, 0.9 mmol) was added. Themixture was warmed to about 25° C. and after about 2 h, saturatedaqueous NH₄Cl was added and the mixture was stirred overnight. Themixture was filtered and the solids were washed with EtOH. The filtratewas concentrated and the residue was purified by chromatography toprovide the title compound L112. Yield: 97 mg (72%). ¹H NMR (400 MHz,CDCl₃) δ 6.72 (s, 1H), 4.72-4.88 (m, 1H), 3.99 (br. s., 1H), 3.74-3.86(m, 1H), 3.54-3.73 (m, 2H), 1.38 (d, 3H).

Preparation 66:(1S,4S,5R)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one (L113)

Step 1. Synthesis of(5aS,6aR,6bS)-3,3-dimethyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one(C150)

A solution of compound P20 (1.0 g, 6.5 mmol) in DCM (40 mL) was cooledto 0° C. and a solution of diazomethane (prepared from 6.7 g ofN-methyl-N-nitrosurea in 65 mL of diethyl ether) was added. Palladiumacetate (72 mg, 0.32 mmol) was added in portions at about 0° C. Themixture was allowed to warm to about 25° C. for about 16 h. The mixturewas filtered and a second portion of diazomethane and palladium acetatewere added and stirred over night. The addition of diazomethane andpalladium acetate were repeated twice more. The mixture was filtered andthe filtrate was concentrated. The residue was purified by HPLC to thetitle compound C150. Yield: 100 mg (9%). ¹H NMR (400 MHz, CD₃OD) δ3.47-3.57 (m, 3H), 1.90-1.98 (m, 1H), 1.75-1.81 (m, 1H), 1.12-1.19 (m,1H), 0.58-0.63 (m, 1H).

Step 2. Synthesis of(1S,4S,5R)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one (L113)

To a stirred solution of compound C150 (95 mg, 0.57 mmol) in 5 mL ofacetonitrile and 1 mL of water was added 4-toluenesulfonic acid (5 mg,0.03 mmol). The reaction mixture was heated at about 90° C. for about 1h. The reaction mixture was cooled to about 25° C., concentrated, andthe residue was purified by chromatography to provide the title compoundL113. Yield: 35 mg (33%). ¹H NMR (400 MHz, CD₃OD) δ 4.61 (br. s, 1H),3.95 (d, 1H), 3.65 (dd, 1H), 3.51 (dd, 1H), 3.34 (dt, 1H), 2.01-2.10 (m,1H), 0.98-1.05 (m, 1H), 0.78-0.83 (m, 1H).

Preparation 67: (1S,2S,5R)-tert-butyl6,6-dichloro-2-(hydroxymethyl)-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate(L114)

Step 1. Synthesis of (1S,2S,5R)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-6,6-dichloro-3-azabicyclo[3.1.0]hexane-3-carboxylate(C151)

To a stirred solution of (S)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(CAS 247200-49-3, 5.0 g, 16 mmol) and benzyltriethyl NH₄Cl (0.73 g, 3.2mmol) in CHCl₃ (100 mL) was added 50% NaOH solution (100 mL). Themixture was stirred at about 25° C. for about 16 h, then diluted withDCM and separated. The aqueous phase was extracted twice with additionalDCM. The combined DCM extracts were washed with water, brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C151. Yield: 3.6 g (57%) ascolorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 3.90-4.09 (m, 1H), 3.81-3.89(m, 1H), 3.73-3.81 (m, 1H), 3.61-3.73 (m, 1H), 3.57 (dd, 1H), 2.28-2.39(m, 1H), 2.22-2.29 (m, 1H), 1.43 (d, 9H), 0.90 (d, 9H), 0.03-0.10 (m,6H)

Step 2. Synthesis of (1S,2S,5R)-tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-6,6-dichloro-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate(C152)

Sodium periodate (654 mg, 3.0 mmol) was dissolved in water (6.5 mL) anda catalytic amount of hydrated ruthenium dioxide was added. Afterstirring for 5 min, a solution of compound C151 (400 mg, 1.0 mmol) inEtOAc (6.5 mL) was added. The resulting mixture was stirred vigorouslyovernight. The phases were separated and the EtOAc phase was washed withsodium bisulfate solution, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C152. Yield: 290 mg (70%). ¹H NMR (400 MHz, CDCl₃) δ4.16-4.21 (m, 1H), 3.92-3.98 (m, 1H), 3.85-3.91 (m, 1H), 2.82 (dd, 1H),2.56 (d, 1H), 1.51 (s, 9H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H).

Step 3. Synthesis of (1S,2S,5R)-tert-butyl6,6-dichloro-2-(hydroxymethyl)-4-oxo-3-azabicyclo-[3.1.0]hexane-3-carboxylate(L114)

Compound C152 (290 mg, 0.7 mmol) in THF (8 mL) was treated withtetrabutylammonium fluoride (1 M, 1.4 mL) at about 25° C. The mixturewas stirred at about 25° C. for about 4 h, then water was added and themixture was extracted twice with EtOAc (15 mL each). The combined EtOAcextracts were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound L114. Yield: 124 mg (59%). ¹H NMR (400 MHz, CDCl₃) δ 5.57(br. s., 1H), 4.19-4.27 (m, 1H), 4.08-4.15 (m, 1H), 3.90 (t, 1H), 2.81(d, 1H), 2.55 (d, 1H), 1.51 (s, 9H).

Preparation 68: (S)-5-((S)-1-hydroxyethyl)pyrrolidin-2-one (L115)

Step 1. Synthesis of (S)-5-((S)-1-hydroxyethyl)pyrrolidin-2-one (L115)

A mixture of(S)-5-((S)-1-hydroxyethyl)-1-(9-phenyl-9H-fluoren-9-yl)pyrrolidin-2-one(CAS 191406-21-0, 750 mg, 2.0 mmol) and palladium on carbon (350 mg) inMeOH (36 mL) and EtOAc (36 mL) was hydrogenated at about 40 psi forabout 30 h at about 25° C. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by chromatography to provide thetitle compound L115. Yield: 220 mg (84%). ¹H NMR (400 MHz, dmso-d₆) δ7.51 (br. s, 1H), 4.66 (d, 1H), 3.41-3.45 (m, 1H), 3.31-3.36 (m, 1H),2.08-2.13 (m, 2H), 1.93-2.05 (m, 1H), 1.62-1.70 (m, 1H), 0.98 (d, 3H).

Preparation 69:(4S,5S)-4-(2-fluoroethyl)-5-(hydroxymethyl)pyrrolidin-2-one (L116)Step 1. Synthesis of(7R,7aS)-7-(2-hydroxyethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C153)

Cyclohexene (4.3 mL, 42 mmol) was added to a solution of borane in THF(1 M, 21.1 mL) at about 0° C. After 30 min, the mixture was warmed toabout 25° C. and stirred approximately 30 min longer. After cooling toabout 0° C., a solution of compound C55 (2.55 g, 14.1 mmol) in DCM (70mL) was added dropwise over about 15 min. After about 90 minutes at 0°C., water (40 mL) was added and the mixture was stirred forapproximately 30 min at about 0° C. The mixture was partiallyconcentrated to remove about 50 mL of DCM and THF (20 mL) was added.Sodium perborate tetrahydrate (8.93 g, 56 mmol) was added and themixture was stirred overnight while being allowed to warm to about 20°C. The phases were separated and the aqueous phase was extracted 5 timeswith DCM and 3 times with MTBE. The combined DCM and MTBE extracts weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography to provide the title compound C153. Yield: 2.04 g(73%). ¹H NMR (400 MHz, CDCl₃) δ 4.38 (dt, 1H), 3.91 (dd, 1H), 3.68-3.77(m, 2H), 3.60-3.68 (m, 1H), 2.94 (dd, 1H), 2.53-2.65 (m, 1H), 2.34 (dd,1H), 1.71-1.82 (m, 1H), 1.65 (s, 3H), 1.51-1.62 (m, 2H), 1.48 (s, 3H).

Step 2. Synthesis of(7S,7aS)-7-(2-fluoroethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C154)

To a solution of compound C153 (1.43 g, 7.2 mmol) in DCM (36 mL) atabout 0° C. were added 2,6-lutidine (2.09 mL, 17.9 mmol), DAST (1.75 mL,14.4 mmol), and triethylamine trihydrofluoride (1.16 mL, 7.2 mmol). Themixture was stirred overnight while warming to about 20° C., then wasadded dropwise into saturated aqueous NaHCO₃. The mixture was extracted4 times with DCM. The combined DCM extracts were dried over Na₂SO₄,filtered and concentrated. The residue was purified by chromatography toprovide the title compound C154. Yield: 1.06 g (73%). ¹H NMR (400 MHz,CD₃OD) δ 4.55-4.52 (m, 1H), 4.47-4.40 (m, 2H), 3.92 (dd, 1H), 3.78-3.73(m, 1H), 2.99 (dd, 1H), 2.66-2.58 (m, 1H), 2.36 (dd, 1H), 2.01-1.86 (m,1H), 1.74-1.61 (m, 1H), 1.60 (s, 3H), 1.44 (s, 3H). ¹⁹F NMR (376 MHz,CD₃OD) δ −221.50.

Step 3. Synthesis of4S,5S)-4-(2-fluoroethyl)-5-(hydroxymethyl)pyrrolidin-2-one (L116)

To a stirred solution of compound C154 (130 mg, 0.65 mmol) in 6.5 mL ofacetonitrile and 1.3 mL of water was added TFA (5 uL, 0.07 mmol). Thereaction mixture was heated at about 90° C. for about 1 h. The reactionmixture was cooled to about 25° C., concentrated, then twice redissolvedin acetonitrile and water and concentrated to provide the title compoundL116. Yield: 90 mg (86%). ¹H NMR (400 MHz, CD₃OD) δ 4.63-4.51 (m, 1H),4.51-4.37 (m, 1H), 3.70-3.57 (m, 3H), 2.72 (m, 1H), 2.38-2.18 (m, 2H),2.14-1.95 (m, 1H), 1.95-1.73 (m, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ−220.91.

Preparation 70:(4R,5S)-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one (L117)

Step 1. Synthesis of(7R,7aS)-7-(1,2-dihydroxyethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C155)

To a solution of compound C55 (1.50 g, 8.3 mmol) in acetone (30 mL) andH₂O (3 mL) was added N-methylmorpholine-N-oxide (1.38 g, 11.8 mmol)followed by osmium tetroxide (31 mg, 0.12 mmol) at about 25° C. Themixture was stirred at about 25° C. for about 3 h, then concentrated.The residue was purified by chromatography to provide the title compoundC155 as a mixture of two diastereomers. Yield: 1.47 g (82%).

Step 2. Synthesis of(7R,7aS)-7-(hydroxymethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C156)

To a solution of compound C155 (2.00 g, 9.3 mmol) in MeCN (50 mL) wasadded water (5 mL) followed by sodium periodate (2.19 g, 10.2 mmol) atabout 25° C. The mixture was stirred at about 25° C. for 1 h, thencooled to about 0° C. and treated with NaBH₄ (538 mg, 13.9 mmol) andstirred for about 1 h. The mixture was filtered, concentrated, and theresidue was taken up in DCM and filtered. The filtrate was concentratedto provide the title compound C156. Yield: 1.69 g (98%). ¹H NMR (400MHz, CD₃OD) δ 4.43 (td, 1H), 3.98-3.84 (m, 2H), 3.63-3.48 (m, 2H), 2.98(dd, 1H), 2.59-2.49 (m, 1H), 2.27 (dd, 1H), 1.59 (s, 3H), 1.43 (s, 3H).

Step 3. Synthesis of(7R,7aS)-7-(fluoromethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C157)

To a solution of compound C156 (1.70 g, 9.3 mmol) in DCM (20 mL) atabout 0° C. were added 2,6-lutidine (2.7 mL, 23 mmol), DAST (2.3 mL,18.6 mmol), and triethylamine trihydrofluoride (1.5 mL, 9.3 mmol). Themixture was stirred at about 25° C. for about 18 h. The reaction wasquenched with saturated aqueous NaHCO₃ and extracted with DCM. Thecombined DCM extracts were dried over Na₂SO₄, filtered and concentrated.The residue was purified by chromatography to provide the title compoundC157. Yield: 800 mg (46%). ¹H NMR (400 MHz, CDCl₃) δ 4.34-4.63 (m, 3H),4.01 (dd, 1H), 3.79-3.87 (m, 1H), 3.03 (ddd, 1H), 2.72-2.85 (m, 1H),2.26 (dd, 1H), 1.67 (s, 3H), 1.51 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ−218.27.

Step 4. Synthesis of(4R,5S)-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one (L117)

To a stirred solution of compound C157 (87 mg, 0.46 mmol) in 4 mL ofacetonitrile and 1 mL of water was added TFA (0.1 mL, 1.4 mmol). Thereaction mixture was heated at about 90° C. for about 1 h. The reactionmixture was cooled to about 25° C., filtered, concentrated, thenredissolved in MeOH and toluene and concentrated. The residue wasdissolved in MeOH and toluene and concentrated several more times toprovide the title compound L117. Yield: 57 mg (83%). ¹H NMR (400 MHz,CD₃OD) δ 4.47-4.75 (m, 2H), 3.73-3.82 (m, 1H), 3.58-3.73 (m, 2H), 2.96(td, 1H), 2.31 (qd, 2H). ¹⁹F NMR (376 MHz, CD₃OD) δ −222.48.

Preparation 71:(3S,4R,5S)-3-fluoro-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L118) Step 1. Synthesis of(6S,7R,7aS)-6-fluoro-7-(fluoromethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C158)

A solution of compound C157 (730 mg, 3.9 mmol) in THF (20 mL) was slowlytreated with LDA (2 M, 2.9 mL) at −78° C. After 30 min at −78° C., apre-cooled (−78° C.) solution of NFSI (1.97 g, 6.2 mmol) in THF (20 mL)was added via cannula. Immediately after the complete addition of NFSI,the reaction was quenched with water at −78° C. and allowed to warm to25° C. The solution was diluted with additional water (15 mL) andextracted with MTBE (50 mL). The aqueous phase was again extracted withMTBE (50 mL) and the combined MTBE extracts were dried over Na₂SO₄,filtered and concentrated. The residue was purified by chromatography toprovide the title compound C158. Yield: 120 mg (15%). ¹H NMR (400 MHz,CDCl₃) δ 5.36 (dd, 1H), 4.78-4.65 (m, 1H), 4.65-4.53 (m, 1H), 4.17-4.04(m, 2H), 3.96-3.86 (m, 1H), 3.28-3.08 (m, 1H), 1.69 (s, 3H), 1.50 (s,3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −202.40, −228.51. There was alsoobtained(6R,7R,7aS)-6-fluoro-7-(fluoromethyl)-3,3-dimethyltetrahydropyrrolo-[1,2-c]oxazol-5(3H)-one(C159). Yield: 540 mg (68%). ¹H NMR (400 MHz, CDCl₃) δ 4.95 (dd, 1H),4.65 (d, 1H), 4.50-4.58 (m, 2H), 4.04 (ddd, 1H), 3.75 (ddd, 1H),2.76-2.96 (m, 1H), 1.65 (s, 3H), 1.54 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃)δ −187.58, −223.88.

Step 2. Epimerization of(6R,7R,7aS)-6-fluoro-7-(fluoromethyl)-3,3-dimethyltetrahydropyrrolo-[1,2-c]oxazol-5(3H)-one(C159)

LDA (2 M, 0.89 mL) was added to a solution of compound C159 (240 mg, 1.2mmol) in toluene (3 mL) at −78° C. The mixture was stirred for 30 min,after which a −78° C. solution of BHT (517 mg, 2.3 mmol) in toluene (6mL) was added. Immediately after the addition of BHT, water (2 mL) wasadded and the mixture was allowed to warm to 20° C. EtOAc was added andthe aqueous phase was extracted again with EtOAc. The combined EtOAcextracts were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography to provide compound C158. Yield: 113 mg(47%).

Step 3. Synthesis of(3S,4R,5S)-3-fluoro-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L118)

To a stirred solution of compound C158 (370 mg, 1.8 mmol) in 12 mL ofacetonitrile and 3 mL of water was added silica bound 4-toluenesulfonicacid (132 mg, 0.09 mmol). The reaction mixture was heated at 80° C. for2 h. The reaction mixture was cooled to 25° C. and concentrated toprovide the title compound L118. Yield: 250 mg (84%). ¹H NMR (400 MHz,CD₃OD) δ 5.03 (dd, 1H), 4.81-4.74 (m, 1H), 4.74-4.61 (m, 1H), 3.86-3.77(m, 1H), 3.69 (dd, 1H), 3.61 (dd, 1H), 3.15-2.94 (m, 1H). ¹⁹F NMR (376MHz, CD₃OD) δ −203.74, −227.31.

Preparation 72:(3S,4S,5S)-3-fluoro-4-(2-fluoroethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L121) Step 1. Synthesis of(6S,7S,7aS)-6-fluoro-7-(2-fluoroethyl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C160)

A solution of compound C154 (1.01 g, 5.0 mmol) in THF (25 mL) was slowlytreated with LDA (2 M, 3.8 mL) at −78° C. After 30 min at −78° C., apre-cooled (−78° C.) solution of NFSI (2.58 g, 8.0 mmol) in THF (25 mL)was added via cannula. After 20 min, the reaction was quenched withwater (4 mL) at −78° C. and allowed to warm to 25° C. The solution wasdiluted with additional water (25 mL) and extracted with MTBE (25 mL).The aqueous phase was extracted 3 times with MTBE (20 mL each) and thecombined MTBE extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound C160. Yield: 350 mg (32%).1H NMR (400 MHz, CDCl₃) δ 5.29(dd, 1H), 4.48-4.66 (m, 1H), 4.51 (ddd, 1H), 4.11 (dt, 1H), 3.99-4.06(m, 1H), 3.71-3.79 (m, 1H), 2.98-3.08 (m, 1H), 1.75-2.07 (m, 2H), 1.68(s, 3H), 1.49 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −198.87, −219.80.There was also obtained(6R,7S,7aS)-6-fluoro-7-(2-fluoroethyl)-3,3-dimethyltetrahydropyrrolo-[1,2-c]oxazol-5(3H)-one(C161). Yield: 516 mg (47%). ¹H NMR (400 MHz, CDCl₃) δ 4.83 (dd, 1H),4.58-4.64 (m, 1H), 4.44-4.53 (m, 2H), 3.99 (dd, 1H), 3.57 (dd, 1H),2.64-2.79 (m, 1H), 1.72-2.01 (m, 2H), 1.65 (s, 3H), 1.51 (s, 3H). ¹⁹FNMR (376 MHz, CDCl₃) δ −185.95, −219.45.

Step 2. Epimerization of(6R,7S,7aS)-6-fluoro-7-(2-fluoroethyl)-3,3-dimethyltetrahydropyrrolo-[1,2-c]oxazol-5(3H)-one(C161)

LDA (2 M, 0.34 mL) was added to a solution of compound C161 (100 mg,0.46 mmol) in toluene (2 mL) at about −78° C. The mixture was stirredfor 30 min, after which a about −78° C. solution of BHT (201 mg, 0.91mmol) in toluene (4 mL) was added. Immediately after the addition ofBHT, water (4 mL) was added and the mixture was allowed to warm to about20° C. MTBE was added and the phases were separated. The MTBE extractwas dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography to provide compound C160. Yield: 36 mg (36%).

Step 3. Synthesis of(3S,4S,5S)-3-fluoro-4-(2-fluoroethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L121)

To a stirred solution of compound C160 (460 mg, 0.39 mmol) in 21 mL ofacetonitrile and 5 mL of water was added TFA (8 uL, 0.1 mmol). Thereaction mixture was heated at 90° C. for 1 h. The reaction mixture wascooled to 25° C., concentrated, then twice redissolved in acetonitrileand water and concentrated. The residue was triturated with CHCl₃ toprovide the title compound L121. Yield: 270 mg (72%). ¹H NMR (400 MHz,CD₃OD) δ 4.86 (dd, 1H), 4.62-4.70 (m, 1H), 4.50-4.58 (m, 1H), 3.71-3.82(m, 2H), 3.50-3.57 (m, 1H), 2.78 (m, 1H), 1.95-2.10 (m, 2H). ¹⁹F NMR(376 MHz, CD₃OD) δ −194.88, −217.30.

Preparation 73: (±)-(3R,4R)-tert-butyl3-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate (L122)

Step 1. Synthesis of (±)-(3R,4R)-ethyl1-benzyl-4-(trifluoromethyl)pyrrolidine-3-carboxylate (C164)

To a solution of ethyl (E)-4,4,4-trifluorocrotonate (CAS 25597-16-4, 6.0g, 36 mmol) and TFA (0.55 mL, 7 mmol) in DCM (60 mL) at about 0° C. wasadded N-(methoxymethyl)-N-[(trimethylsilyl)methyl]-benzenemethanamine(CAS 93102-05-7, 16.85 g, 71 mmol) over a period of about 20 minutes.The reaction mixture was then heated at reflux for 16 h. It was dilutedwith DCM (100 mL), washed with saturated aqueous NaHCO₃ solution (2×100mL), water (100 mL), and brine (50 mL). The DCM extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C164. Yield: 10.5 g (99%).¹H NMR (400 MHz, dmso-d₆) δ 7.23-7.34 (m, 5H), 4.07-4.15 (m, 2H), 3.64(d, 1H), 3.54 (d, 1 H), 3.35-3.41 (m, 1H), 3.12 (q, 1H), 2.81 (t, 2H),2.69-2.73 (m, 1H), 2.55-2.59 (m, 1H), 1.17 (t, 3H).

Step 2. Synthesis of (±)-(3R,4R)-1-tert-butyl 3-ethyl4-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (C165)

To a solution of compound C164 (2.0 g, 6.6 mmol) and dit-t-butyldicarbonate (2.3 mL, 9.97 mmol) in EtOH (30 mL) was added palladiumhydroxide on carbon (600 mg) and the mixture was stirred under ahydrogen atmosphere (1 atm) for about 16 h. The mixture was filtered andthe filtrate was concentrated. The residue was purified bychromatography to provide the title compound C165. Yield: 1.8 g (87%).¹H NMR (400 MHz, dmso-d₆) δ 4.13 (q, 2H), 3.60-3.68 (m, 2H), 3.43-3.59(m, 2H), 3.25-3.39 (m, 2H), 1.39 (s, 9H), 1.19 (t, 1H).

Step 3. Synthesis of (±)-(3R,4R)-tert-butyl3-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate (L122)

A solution of compound C165 (1.8 g, 5.8 mmol) in THF (20 mL) was cooledto about 0° C. and lithium borohydride (630 mg, 29 mmol) was added inportions. The mixture was heated under reflux for about 16 hours. It wasthen cooled to about 25° C. and diluted with EtOAc (50 mL). The EtOAcextract was washed with water, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography to provide thetitle compound L122. Yield: 1.3 g (83%). ¹H NMR (400 MHz, dmso-d₆) δ4.95 (t, 1H), 3.55 (br. s, 1H), 3.33-3.46 (m, 4H), 3.14-3.19 (m, 1H),3.02 (br. s, 1H), 2.44 (br. s, 1H), 1.39 (s, 9H).

Preparation 74:(3S,4S,5S)-3,4-d₂-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L123)

Step 1. Synthesis of(S)-7-ethyl-6-fluoro-3,3-dimethyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one(C172)

A solution of compound C62 (2.00 g, 9.9 mmol) and diphenyl diselenide(3.32 g, 10.4 mmol) in THF (40 mL) was treated with lithiumhexamethyldisilazide (1 M, 10.4 mL) at about 0° C. The mixture was keptat about 0° C. for about 30 min, then was warmed to about 25° C. forabout 3 h. Water and EtOAc were added and the phases were separated. Theaqueous phase was extracted with EtOAc, and the combined EtOAc extractswere dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in DCM (100 mL) and pyridine (5.1 mL, 63 mmol) and was treatedwith hydrogen peroxide (30%, 4.8 mL, 47 mmol) at about 0° C. The mixturewas stirred at about 0° C. for about 30 min, then allowed to warm toabout 25° C. for about 2 h. The mixture was washed with saturatedaqueous NaHCO₃, 1 M NaOH (twice), water, and brine. The DCM extract wasdried over MgSO₄, filtered and concentrated. The residue was purified bychromatography to provide the title compound C172. Yield: 1.56 g (55%).¹H NMR (400 MHz, CDCl₃) δ 4.36 (dt, 1H), 4.21 (dd, 1H), 3.27-3.37 (m,1H), 2.31-2.50 (m, 2H), 1.67 (s, 3H), 1.57 (s, 3H), 1.16 (t, 3H).

Step 2. Synthesis of(3S,4S,5S)-3,4-d₂-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(L123)

A solution of compound C172 (1.20 g, 6.0 mmol) in ethanol-d₁ (50 mL) wastreated with a rhodium on carbon catalyst (5 mg) and stirred under adeuterium atmosphere at a pressure of 1 atmosphere and a temperature ofabout 20° C. for about 2 h. The mixture was filtered and concentrated.The residue was purified by chromatography to provide the title compoundL123. Yield: 250 mg (25%). ¹H NMR (400 MHz, CDCl₃) δ 7.02 (br. s., 1H),3.72-3.82 (m, 2H), 3.55-3.66 (m, 1H), 2.61 (t, 1H), 1.59-1.71 (m, 1H),1.44-1.57 (m, 1H), 1.06 (t, 3H).

Preparation 75:(3R,4R,5S)-3-fluoro-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L124) Step 1. Synthesis of(3R,4R,5S)-3-fluoro-4-(fluoromethyl)-5-(hydroxymethyl)pyrrolidin-2-one(L124)

To a stirred solution of compound C159 (70 mg, 0.34 mmol) in 4 mL ofacetonitrile and 1 mL of water was added TFA (3 uL, 0.03 mmol). Thereaction mixture was heated at 90° C. for 1 h. The reaction mixture wascooled to 25° C. and concentrated to provide the title compound L124.Yield: 69 mg (100%). ¹H NMR (400 MHz, CD₃OD) δ 5.07 (dd, 1H) 4.89-4.80(m, 3H), 4.79-4.67 (m, 1H), 3.76 (td, 1H), 3.67-3.58 (m, 2H), 3.13-2.92(m, 1H). ¹⁹F NMR (400 MHz, CD₃OD) δ −193.07, −226.18.

Preparation 76: 4-(hydroxymethyl)-5-azaspiro[2.4]heptan-6-one (L125)

Step 1. Synthesis of ethyl 2-cyclopropylideneacetate (C180)

To a stirred solution of 1-ethoxy-1-[(trimethylsilyl)oxy]-cyclopropane(CAS 27374-25-0, 10 g, 57 mmol) in toluene (50 mL) was added(carbethoxymethylene)triphenylphosphorane (CAS 1099-45-2, 26 g, 74 mmol)followed by benzoic acid (0.91 g, 7.5 mmol) at about 25° C. The mixturewas heated overnight at about 90° C., then cooled and concentrated. Theresidue was purified by chromatography to provide the title compoundC180. Yield: 3.2 g (44%). ¹H NMR (400 MHz, CDCl₃) δ 6.22 (s, 1H), 4.14(q, 2H), 1.40-1.46 (m, 2H), 1.27 (t, 3H), 1.20-1.24 (m, 2H).

Step 2. Synthesis of ethyl 2-(1-(nitromethyl)cyclopropyl)acetate (C181)

A solution of compound C180 (2.3 g, 18 mmol), nitromethane (4.90 mL, 91mmol) and DBU (2.73 mL, 18 mmol) in MeCN (50 mL) was heated overnight atabout 60° C. The mixture was cooled, diluted with EtOAc, and washed withsaturated aqueous NH₄Cl solution. The EtOAc was separated and theaqueous phase was extracted with EtOAc. The combined EtOAc extracts weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography to provide the title compound C181. Yield: 1.7 g(50%). ¹H NMR (400 MHz, CDCl₃) δ 4.41 (s, 2H), 4.15 (q, 2H), 2.48 (s,2H), 1.26 (t, 3H), 0.80-0.83 (m, 2H), 0.70-0.74 (m, 2H).

Step 3. Synthesis of ethyl2-(1-(2-hydroxy-1-nitroethyl)cyclopropyl)acetate (C182)

A solution of compound C181 (2.5 g, 13 mmol), paraformaldehyde (0.802 g,26 mmol) and potassium fluoride (78 mg, 1.3 mmol) in 2-propanol (30 mL)was stirred for about 36 h at about 25° C. and then concentrated. Theresidue was purified by chromatography to provide the title compoundC182. Yield 1.1 g (38%). ¹H NMR (400 MHz, CDCl₃) δ 4.14 (q, 2H),4.03-4.10 (m, 2H), 3.92-3.96 (m, 1H), 3.16-3.20 (m, 1H), 2.86 (d, 1H),2.23 (d, 1H), 1.27 (t, 3H), 0.90-0.99 (m, 2H), 0.79-0.83 (m, 1H),0.64-0.68 (m, 1H).

Step 4. Synthesis of 4-(hydroxymethyl)-5-azaspiro[2.4]heptan-6-one(L125)

To a solution of compound C182 (600 mg, 2.7 mmol) in EtOH (10 mL) wasadded platinum dioxide (60 mg) and the mixture was stirred under ahydrogen atmosphere (1 atm) for about 20 h at about 25° C. The mixturewas filtered and the filtrate was heated at about 80° C. for about 24 h,then concentrated. The residue was purified by chromatography to providethe title compound L125. Yield: 220 mg (56%). ¹H NMR (400 MHz, dmso-d₆)δ 7.70 (br. s., 1H), 4.66 (t, 1H), 3.25-3.39 (m, 2H), 3.08 (t, 1H), 2.39(d, 1H), 1.89 (d, 1H), 0.73-0.86 (m, 1H), 0.40-0.61 (m, 3H).

Preparation 76:1-{[(2R,3R,4S)-3-ethyl-4-fluoro-3-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide

Step 1

Sterile medium was prepared using deionized water containing dextrose(10 g/L), glycerol (20 g/L), Difco Yeast Extract (5 g/L), Nutrisoy flour(5 g/L), NaCl (5 g/L), K₂HPO₄ (5 g/L), P2000 (1 ml/L), pH adjusted to7.0 prior to autoclaving to sterilize.

Step 2

Streptomyces spectabilis ATCC 27465 was grown in 25 mL of this mediumwhich had been added to each of three sterile Nalgene flasks (250 mL,baffled, vented closures) on a 2″ throw rotary shaker at 30° C., 210rpm, for two days. The contents of each flask were asepticallytransferred to each of three sterile 2 L Nalgene flasks (baffled, ventedclosures) containing 400 mL of the same sterile medium then incubated asabove. After two days, 16 mL of a solution of1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamidein DMSO (5 mg/mL) was added to each flask. Incubation continued asabove; flasks were aseptically sampled every 24 hours. After three days,contents of the flasks were combined and extracted twice with an equalvolume of ethyl acetate. The organic phases were combined, dried withanhydrous sodium sulfate then concentrated under vacuum to yield 3.7 gof brown oil.

Step 3

High performance liquid preparative chromatography using a 0.1%trifluoroacetic acid in water with acetonitrile gradient on a PhenomenexLuna phenyl-hexyl column was utilized to isolate compounds from theabove preparation. Time based fraction collection was used to collectall peaks of interest. Each sample was dried and tested by LCMS toconfirm retention time identification and the parent ion of m/z=378daltons.1-{[(2R,3R,4S)-3-ethyl-4-fluoro-3-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide(Example 196): ¹H NMR (600 MHz, dmso-d₆) δ 8.85 (s, 1H), 8.17 (s, 1H),7.91 (d, 1H), 7.85 (br. s, 1H), 7.71 (s, 2H), 7.45 (d, 1H), 4.58 (dd,1H), 4.48 (d, 1H), 4.30 (dd, 1H), 3.98 (s, 3H), 3.87 (dd, 1H), 1.72 (q,2H), 1.01 (t, 3H).

The following two examples were also prepared:

1-{[(3S,4S)-3-ethyl-4-fluoro-2-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide(Example 197), as a mixture of diastereomers: Major diastereomer: ¹H NMR(600 MHz, dmso-d₆) δ 9.25 (s, 1H), 8.18 (s, 1H), 7.92 (d, 1H), 7.6 (s,1H), 7.72 (s, 1H), 7.6 (s, 1H), 7.54 (s, 1H), 4.96 (dd, 1H), 4.5 (dd,2H), 3.98 (s, 3H), 2.47 (m, 1H), 1.67 (m, 1H), 0.99 (t, 3H). Minordiastereomer ¹H NMR (600 MHz, dmso-d₆) δ 9.18 (s, 1H), 8.16 (s, 1H),7.91 (d, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H),5.14 (dd, 1H), 4.5 (dd, 2H), 3.92 (s, 3H), 2.39 (m, 1H), 1.58 (m, 1H),0.99 (t, 3H).

1-{[(2S,3R,4S)-4-fluoro-3-(1-hydroxyethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide(Example 198): ¹H NMR (600 MHz, dmso-d₆) δ 9.0 (s, 1H), 8.17 (s, 1H),7.91 (d, J 1H), 7.86 (br s, 1H), 7.76 (s, 1H), 7.71 (bs, 1H), 7.44 (d,1H), 4.94 (d, 1H), 4.83 (dd, 1H), 4.60 (dd, 1H), 4.26 (dd, 1H), 4.07 (m,1H), 3.99 (m, 1H), 3.916 (m, 1H), 2.56 (m, 1H), 1.23 (d, 3H).

Methods

The Methods set forth hereinbelow are intended only to exemplify variousaspects and embodiments of the invention, and are not intended to limitthe scope of the claimed invention in any way. It will be apparent toone skilled in the art that the Methods described below may be modifiedin various ways, for example by changing reaction solvents or volumes,by substituting similar reagents to those described, or by substitutingsimilar catalysts to those described.

Method 1

A reactant B such as tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (CAS 123855-51-6, commerciallyavailable, 28 mg, 0.13 mmol) was dissolved in 0.5 mL of DMSO and areactant A such as 1-chloro-7-isopropoxyisoquinoline-6-carbonitrile (P2)(0.2 M in DMSO, 0.5 mL, 0.10 mmol) was added. The mixture was thentreated with potassium tert-butoxide (1 M in THF, 0.13 mL, 0.13 mmol).The reaction mixture was heated at about 50° C. to about 100° C. forabout 2 to 16 hours until the reaction was judged to be complete. Themixture was then cooled to about 25° C. and filtered and the filtratewas concentrated. The residue may be used directly for subsequent work,or it may be purified by chromatography or HPLC.

Method 2

To a solution of a reactant B such as(3S,5S)-3-fluoro-5-(hydroxymethyl)-3-methyl-pyrrolidin-2-one (L10) (314mg, 2.1 mmol) in 15 mL of DMF was added sodium hydride (60% in mineraloil, 342 mg, 8.6 mmol) at about 25° C. and the mixture was stirred forabout 15 minutes. A reactant A such as1-chloro-7-methoxyisoquinoline-6-carbonitrile (P1) (513 mg, 2.3 mmol)was added and stirring was continued for about 16 h. The reaction wasquenched with EtOAc and water at about 0° C. The mixture was extractedwith EtOAc and the EtOAc was separated, washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue may be used directly forsubsequent work, or it may be purified by chromatography or HPLC.

Method 3

A reactant B such as(3R,4S,5S)-5-(hydroxymethyl)-3-methoxy-4-methylpyrrolidin-2-one (L65)(105 mg, 0.66 mmol) and a reactant A such as1-chloro-7-methoxyisoquinoline-6-carbonitrile (P1) (120 mg, 0.55 mmol)were stirred in DMF (15 mL) at about 25° C. A solution of potassiumhexamethyldisilazide (1 M in THF, 1.37 mL) was added dropwise to thereaction mixture. After the addition of potassium hexamethyldisilazidewas complete, the reaction was stirred for approximately an additional50 minutes. The reaction mixture was then poured into a mixture ofsaturated aqueous NH₄Cl solution and EtOAc with vigorous stirring. TheEtOAc was separated, washed with water, brine, dried over Na₂SO₄,filtered and concentrated. The residue may be used directly forsubsequent work, or it may be purified by chromatography or HPLC.

Method 4

A reactant B such as tert-butyl 4-hydroxypiperidine-1-carboxylate (CAS109384-19-2, commercially available, 50 mg, 0.2 mmol), a reactant A suchas 4-chloro-6-isopropoxy-quinoline-7-carboxamide (P4) (30 mg, 0.1 mmol),and cesium carbonate (300 mg, 0.9 mmol) were combined in a smallmicrowave vessel and diluted with 1 mL of DMSO. The vessel was cappedand heated in a microwave reactor at about 150° C. for about 15 minutes.The reaction mixture was then diluted with EtOAc and water and thephases were separated. The aqueous phase was extracted three times withEtOAc and the combined EtOAc extracts were dried and concentrated. Theresidue may be used directly for subsequent work, or it may be purifiedby chromatography or HPLC. Potassium carbonate may be used in place ofcesium carbonate in some instances.

Method 5

Triphenylphosphine (1.59 g, 5.9 mmol) was added to a suspension of areactant B such as (4R,5S)-5-(hydroxymethyl)-4-methylpyrrolidin-2-one(L36) (393 mg, 2 mmol) and a reactant A such as5-hydroxy-3-methoxy-2-naphthamide (P5) (430 mg, 2 mmol) in 10 mL of THF.Diisopropyl azodicarboxylate (0.84 g, 3.9 mmol) was added dropwise. Themixture was stirred at about 20° C. for 6 days and then concentrated.The residue may be used directly for subsequent work, or it may bepurified by chromatography or HPLC.

Method 6

A solution of a reactant B such as(5S)-5-(hydroxymethyl)-3-methoxypyrrolidin-2-one (L25) (264 mg, 2 mmol)in 15 mL of DCM was treated with p-toluenesulfonyl chloride (760 mg, 4mmol) and DMAP (512 mg, 4 mmol). The reaction mixture was stirred forabout 12 h at about 25° C. The mixture was washed with water (15 mL).The DCM was dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel chromatography to give 312 mg (52%) of theintermediate p-toluenesulfonate ester of L25.

To a solution of the intermediate p-toluenesulfonate ester of L25prepared above (166 mg, 0.55 mmol) in dry DMF (5 mL) was added cesiumcarbonate (357 mg, 1.1 mmol) and a reactant A such as5-hydroxy-3-methoxy-2-naphthamide (P5) (132 mg, 0.6 mmol). The mixturewas stirred for about 2 h at about 65° C. The DMF was evaporated, andthe residue was stirred with EtOAc and the mixture was filtered. Thefilter cake was washed with water (5 mL×2). The filter cake was driedunder vacuum, treated with EtOAc and filtered. The residue may be useddirectly for subsequent work, or it may be purified by chromatography orHPLC.

Method 7

A solution of a reactant such as tert-butyl4-(((6-cyano-7-isopropoxyisoquinolin-1-yl)oxy)methyl)-piperidine-1-carboxylate(42 mg, 0.10 mmol) in DMSO (1 mL) was treated with powdered K₂CO₃ (41mg, 0.30 mmol) followed by 30% hydrogen peroxide solution (0.2 mL, 1.8mmol). The mixture was heated at about 40° C. to 60° C. for about 15minutes to 16 hours until the reaction was judged to be complete. Themixture was then cooled to about 25° C. and filtered and the filtratewas concentrated. The residue may be used directly for subsequent work,or it may be purified by chromatography or HPLC. Sodium hydroxide orpotassium hydroxide may be substituted for K₂CO₃ in some cases.

Method 8

A solution of a reactant such as1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carbonitrile(200 mg, 0.5 mmol) in concentrated H₂SO₄ (1.5 mL) was warmed to about55° C. for about two hours, then cooled to about 20° C. The reactionmixture was added dropwise with vigorous stirring to 7.3 mL of ice coldconcentrated ammonium hydroxide with cooling in ice. The precipitatedsolid was filtered and washed with water, heptane, ether, and driedunder vacuum. The residue may be used directly for subsequent work, orit may be purified by chromatography or HPLC.

Method 9

A solution of a reactant such as1-(((2S,4R)-4-((benzyloxy)methyl)-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-isopropoxyisoquinoline-6-carboxamide(20 mg, 0.44 mmol) in MeOH (0.46 mL) was treated with a palladium oncarbon catalyst (5 mg) and stirred under a hydrogen atmosphere at apressure of about 1 to 5 atmospheres and a temperature of about 20° C.to 65° C. The mixture was then cooled to about 20° C. and filtered andthe filtrate was concentrated. The residue may be used directly forsubsequent work, or it may be purified by chromatography or HPLC.

Method 10

A solution of a reactant such as tert-butyl4-(((6-carbamoyl-7-isopropoxyisoquinolin-1-yl)oxy)methyl)piperidine-1-carboxylate(44 mg, 0.1 mmol) in 1.0 to 2.0 mL of a suitable solvent such as DCM wastreated with either TFA (0.10 mL) or hydrogen chloride (4 M in dioxane,0.4 mL). The reaction mixture was was heated at about 30° C. to 40° C.for about 1 to 4 hours until the reaction was judged to be complete. Themixture was then cooled to about 25° C. and concentrated under vacuumand purified using by chromatography or HPLC.

Method 11

A solution of a reactant such as7-isopropoxy-1-(piperidin-4-ylmethoxy)isoquinoline-6-carboxamide (41 mg,0.12 mmol) in DMF (1.0 mL) was treated with cyanoacetic acid (11 mg,0.12 mmol), followed by HATU (47 mg, 0.12 mmol) and Et₃N (35 μL, 0.25mmol). The reaction mixture was heated at about 30° C. to 50° C. forabout 4 to 16 hours until the reaction was judged to be complete. Themixture was then cooled to about 25° C. and concentrated under vacuumand purified by chromatography or HPLC.

Method 12

A solution of a reactant such as1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide(500 mg, 1.4 mmol) in DMF (15 mL) was treated with SelectFluor® (511 mg,1.4 mmol) and heated at about 55° C. for about 24 h. The mixture wasconcentrated, xylene was added, and the mixture was concentrated again.The concentration with xylene was repeated twice more, and the residuewas stirred with EtOAc. The precipitated solid was filtered and washedwith EtOAc, and the EtOAc filtrates were combined, concentrated, andtreated with EtOAc and water. The EtOAc was separated, concentratedunder vacuum and purified by chromatography or HPLC.

Method 13

A solution of a reactant such as (S)-methyl3-methoxy-5-((5-oxopyrrolidin-2-yl)methoxy)-2-naphthoate (366 mg, 1.1mmol) in THF (25 mL) and water (25 mL) was treated with lithiumhydroxide (272 mg, 11.1 mmol). The resulting mixture was stirred atabout 25° C. for about 1 hour, then the mixture was partiallyconcentrated under vacuum to remove the THF. The remaining solution wasacidified with 10% aqueous citric acid, and the resulting precipitatewas collected by filtration, washed with water and dried. The residuemay be used directly for subsequent work, or it may be purified bychromatography or HPLC.

Method 14

A solution of a reactant such as (S)-methyl3-methoxy-5-((5-oxopyrrolidin-2-yl)methoxy)-2-naphthoate (385 mg, 1.2mmol) in THF (25 mL) was treated with Et₃N (0.26 mL, 1.8 mmol) andheated under reflux. The mixture was cooled to about 25° C., then BOPreagent (CAS 56602-33-6, 709 mg, 1.6 mmol) was added. The mixture wasstirred for about 25 min until almost all of the BOP reagent haddissolved, then ammonium hydroxide (15 M, 1.5 mL) was added. After about45 min, the mixture was filtered and the filtrate was concentrated. Theresidue was treated with water, and the resulting precipitate wascollected by filtration, washed with water and dried. The residue may beused directly for subsequent work, or it may be purified bychromatography or HPLC.

Method 15

A solution of a reactant such as(S)-7-isopropoxy-1-((5-oxopyrrolidin-2-yl)methoxy)-isoquinoline-6-carbonitrile(100 mg, 0.3 mmol) in acetonitrile (6.1 mL) was with N-bromosuccinimide(55 mg, 0.3 mmol) was heated at about 60° C. for about 1.5 h. Anadditional portion of N-bromosuccinimide (30 mg 0.14 mmol) was added.After about 30 min, the mixture was cooled to about 25° C. and dilutedwith 10 mL of EtOAc. The EtOAc extract was washed with saturated aqueoussodium thiosulfate (10 mL). The aqueous phase was back-extracted withEtOAc (10 mL), and the combined EtOAc extracts were washed withsaturated aqueous sodium thiosulfate (15 mL), brine (15 mL), dried overNa₂SO₄, filtered and concentrated. The residue may be used directly forsubsequent work, or it may be purified by chromatography or HPLC.

Method 16

A solution of a reactant such as(S)-4-bromo-7-isopropoxy-1-((5-oxopyrrolidin-2-yl)methoxy)isoquinoline-6-carbonitrile(54 mg, 0.1 mmol), palladium bis(triphenylphosphine)-dichloride (19 mg,0.03 mmol), potassium methyltrifluoroborate (25 mg, 0.2 mmol), and K₂CO₃(55 mg, 0.4 mmol) in acetonitrile (0.75 mL) and water (0.5 mL) washeated in a microwave reactor at about 125° C. for about 30 min. Themixture was diluted with EtOAc (10 mL) and washed brine. The aqueousphase was back-extracted with EtOAc (10 mL) and the combined EtOAcextracts were dried over Na₂SO₄, filtered and concentrated. The residuemay be used directly for subsequent work, or it may be purified bychromatography or HPLC.

Method 17

A solution of a reactant such as7-isopropoxy-1-(((3aS,6R,6aR)-1-methoxy-2-oxooctahydrocyclopenta[b]pyrrol-6-yl)oxy)isoquinoline-6-carboxamide(42 mg, 0.1 mmol) in 3.25 mL of acetonitrile and 0.25 mL of water wastreated with molybdenum hexacarbonyl (34 mg, 0.13 mmol). The reactionwas heated at reflux for about 18 h. The mixture cooled to about 25° C.,diluted with MeOH, filtered and concentrated. The residue may be useddirectly for subsequent work, or it may be purified by chromatography orHPLC.

Method 18

A solution of a reactant such as(±)-1-((1R,6S)-3-azabicyclo[4.1.0]heptan-1-ylmethoxy)-7-isopropoxyisoquinoline-6-carboxamide(54 mg, 0.15 mmol) and di-t-butyl dicarbonate (37 mg, 0.17 mmol) in THF(2 mL) and water (2 mL) was stirred for about 45 min at about 25° C.,then diluted with EtOAc and water. The EtOAc was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue may beused directly for subsequent work, or it may be purified bychromatography or HPLC.

Method 19

A solution of a reactant such as(S)-7-isopropoxy-1-((5-oxopyrrolidin-2-yl)methoxy)-isoquinoline-6-carboxamide(272 mg, 0.80 mmol) in 1,4-dioxane (20 mL) was treated with 5 mL of cold50% H₂SO₄. The mixture was heated at about 55° C. for about 24 h, thencooled to about 25° C. and allowed to remain for about 18 h. The dioxanewas separated and the aqueous phase was neutralized to about pH 5 withK2CO3, then extracted repeatedly with EtOAc. The combined dioxane andEtOAc extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue may be used directly for subsequent work, or it may be purifiedby chromatography or HPLC.

Method 20

A solution of a reactant such as(S)-5-(((6-bromo-7-(trifluoromethoxy)isoquinolin-1-yl)oxy)methyl)pyrrolidin-2-one(78 mg, 0.19 mmol) and zinc cyanide (46 mg, 0.38 mmol) in DMF (2.5 mL)was treated with tetrakis(triphenylphosphine)palladium (0) (45 mg, 0.04mmol). The mixture was heated for about 20 min at about 150° C., thendiluted with ice water (35 mL) and filtered. The precipitate wasdissolved in DCM, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue may be used directly for subsequent work, orit may be purified by chromatography or HPLC.

Method 21

A solution of a reactant such as1-(((1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)methoxy)-7-isopropoxyisoquinoline-6-carboxamide(50 mg, 0.10 mmol), aqueous formaldehyde solution (37%, 6 mL) in MeOH(50 mL) was treated with a palladium on carbon catalyst (5 mg) andstirred under a hydrogen atmosphere at a pressure of 1 atmosphere and atemperature of about 20° C. for about 2 h. The mixture was filtered andconcentrated. The residue may be used directly for subsequent work, orit may be purified by chromatography or HPLC.

Method 22

A solution of a reactant such as(S)-4-bromo-7-isopropoxy-1-((5-oxopyrrolidin-2-yl)methoxy)isoquinoline-6-carbonitrile(1.0 g, 2.4 mmol) in 1,4-dioxane (20 mL) was treated with freshly driedpotassium acetate (729 mg, 7.4 mmol), bis(pinacolato diboron) (880 mg,3.5 mmol), and tetrakis(triphenylphosphine)palladium (0) (143 mg, 0.12mmol). The mixture was heated at about 100° C. for about 16 h. Themixture was cooled to about 25° C., filtered, and concentrated. Theresidue may be used directly for subsequent work, or it may be purifiedby chromatography or HPLC.

Examples1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamideStep 1. Synthesis of(7R,7aS)-7-ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C54)

A suspension of copper bromide dimethyl sulfide complex (833 g, 4.05mol) in diethyl ether (6 L) was cooled to about −20 to −30° C., andethylmagnesium bromide solution (2 M in THF, 4.05 L, 8 moles) was addedover about 1 hour allowing the temperature to rise to about −3° C. Afterstirring for about 10 min the slurry was cooled to about −70° C., andTMSCl (382 mL, 3.04 mol) was added drop wise over about 1 h. After about50 min, compound P20 (310 g, 2.02 mol) in 500 mL of MTBE was added tothe mixture drop wise over about 2 hours. The temperature was maintainedat about −72 to −68° C. during the addition. The reaction mixture wasstirred at about −72° C. for about 4 hours, after which time it waswarmed up to about −40° C. over about 16 hours. The reaction mixture wasquenched with half-saturated aqueous NH₄Cl (4 L). After a phaseseparation, the solvent phase was washed with water, dried over Na₂SO₄,filtered, and concentrated. The reaction was performed six times intotal and the combined crude products were purified by silicachromatography to provide the title compound C54. Yield 1.4 kg (63%,based on 12.1 mol of P20). ¹H NMR (400 MHz, CDCl₃) δ 4.34 (dt, 1H), 3.90(dd, 1H), 3.72 (dd, 1H), 2.91 (dd, 1H), 2.31 (dd, 1H), 2.25 (m, 1H),1.65 (s, 3H), 1.52 (d, 1H), 1.48 (s, 3H), 1.27-1.38 (m, 1H), 0.92 (t,3H).

Step 2. Synthesis of(6S,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C61)

A solution of diisopropylamine (184 mL, 1.31 mol) in THF (1.65 L) wascooled to about −20 to −30° C. and treated with n-butyllithium solution(2.5 M in hexanes, 491 mL, 1.23 mol) over about 10 minutes, allowing thetemperature to rise to about −20° C. After stirring for about 10minutes, the solution was cooled to about −70° C., and a solution ofcompound C54 (235 g, 1.17 mol) in THF (588 mL) was added drop wise overabout 30 minutes. The temperature was maintained at about −70 to −60° C.during the addition, and after stirring for about 30 minutes at thistemperature, a solution of NFSI (387 g, 1.23 mol) in 1.2 L THF was addedover about 80 minutes at about −70 to −72° C. After stirring for about 1h at about −70 to −60° C., the reaction was allowed to warm to about 20°C. overnight. The precipitated solids were filtered and washed with THF(1 L). The filtrate was concentrated to an oily residue. This entirereaction was conducted three times at this scale and once using 500 g ofcompound C61. The combined crude products were purified by silicachromatography to provide the title compound C61. Yield: 350 g (27%based on 6.6 mol of C54). ¹H NMR (400 MHz, CDCl₃) δ 5.23 (dd, 1H),3.97-4.11 (m, 2H), 3.68-3.77 (m, 1H), 2.62-2.76 (m, 1H), 1.69-1.79 (m,1H), 1.68 (s, 3H), 1.45-1.52 (m, 3H), 1.28-1.42 (m, 1H), 0.97 (t, 3H).¹⁹F NMR (376 MHz, CDCl₃) δ −199.61. There was also obtained(6R,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-oneC62. Yield: 700 g (54% from 6.6 mol of C54). ¹H NMR (400 MHz, CD₃CN) δ4.78 (dd, 1H), 4.40 (dt, 1H), 3.93 (dd, 1H), 3.56 (dd, 1H), 2.30-2.46(m, 1H), 1.56 (s, 3H), 1.52 (ddd, 1H), 1.42 (s, 3H), 1.35-1.48 (m, 1H),0.97 (t, 3H). ¹⁹F NMR (376 MHz, CD₃CN) δ −185.41.

Step 3. Epimerization of(6R,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(C62)

To a solution of diisopropylamine (310 g, 3.07 mol) in toluene (4 L) wasadded n-butyllithium (2.5 M, 1.22 L, 3.05 mol) dropwise at −30° C. Themixture was maintained at −30° C. for an additional 30 min, then wasadded dropwise to a solution of compound C62 (556 g, 2.77 mol) intoluene (2 L) at −78° C. over 2 h. After the addition was complete, themixture was kept at −78° C. for 30 min more before a solution of BHT(1.26 kg, 5.73 mol) in toluene (5 L) was added dropwise over 3 h,keeping the internal temperature below −65° C. After the addition wascomplete, the mixture was kept at −78° C. for 30 min. The mixture waswarmed to 25° C., water was added, and the toluene was separated. Theaqueous layer was extracted with DCM twice, the combined toluene and DCMextracts were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography to provide compound C61. Yield: 250 g(45%). There was also recovered compound C62. Yield: 150 g (27%).

Step 4. Synthesis of(3S,4S,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (L54)

A solution of compound C61 (90 g, 0.45 mol) in acetonitrile (450 mL) andwater (45 mL) was treated with TFA (6.8 mL, 90 mmol). The mixture waswarmed to about 65° C. over about 1 h, and held at that temperature forabout 3 h. The mixture was then cooled and about 350 mL of solvent wasdistilled by rotary evaporation. The residue was diluted withacetonitrile (400 mL) and evaporated to dryness. Isopropyl acetate (250mL) was added to the residue and the mixture was concentrated again. Theresidue was diluted with heptane (200 mL) and crystallization wasinduced by seeding. The precipitate was filtered in two crops to providethe title compound L54. Yield: 46 g (64%). ¹H NMR (400 MHz, CDCl₃) δ7.59 (br. s., 1H), 4.80 (dd, 1H), 3.69-3.83 (m, 2H), 3.52-3.64 (m, 1H),3.48 (br. s, 1H), 2.27-2.52 (m, 1H), 1.57-1.73 (m, 1H), 1.49 (dt, 1H),1.04 (t, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −198.72.

Step 5. Synthesis of1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carbonitrile(C171)

A mixture of compound L54 (8.00 g, 49.6 mmol) and compound P1 (9.87 g,45.1 mmol) were stirred in DMF (83 mL) and cooled to about −10° C. Asolution of potassium hexamethyldisilazide (1 M in THF, 99 mL, 99 mmol)was added to the reaction mixture over about 45 minutes, maintaining theinternal reaction temperature at about −10° C. After the addition ofpotassium hexamethyldisilazide was complete, the reaction was stirred atabout −10° C. for approximately an additional 30 minutes. A solution of24.9 g of sodium dihydrogen phosphate in 250 mL of water was prepared.The reaction mixture was then poured into 220 mL of this aqueous sodiumdihydrogen phosphate solution and 250 mL of EtOAc with vigorousstirring. The reaction flask was rinsed with the remaining 30 mL of theaqueous sodium dihydrogen phosphate solution and the rinse was added tothe EtOAc mixture. The EtOAc was separated. The aqueous mixture wasextracted three times with EtOAc. The combined EtOAc extracts were driedover MgSO₄, filtered and concentrated. Xylene was added to the residueand the mixture was concentrated. Addition of xylene and subsequentevaporation was carried out two more times to provide the title compoundC171. Yield: 15.37 g (90%). ¹H NMR (400 MHz, dmso-d₆) δ 8.89 (s, 1H),8.50 (s, 1H), 7.98 (d, 1H), 7.80 (s, 1H), 7.41 (d, 1H), 4.90 (dd, 1H),4.56 (dd, 1H), 4.24 (dd, 1H), 4.09 (dt, 1H), 4.03 (s, 3H), 2.62 (m, 1H),1.58 (m, 2H), 1.02 (t, 3H). ¹⁹F NMR (376 MHz, dmso-d₆) 6-199.18.

Step 6. Synthesis of1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide(Example 296)

A mixture of compound C171 (15.37 g, 44.7 mmol) and methanesulfonic acid(218 mL, 3.36 mol) was heated at about 60° C. with stirring for about 26hours. The mixture was then cooled to about 25° C. and slowly added to 1kg of crushed ice with stirring. During the addition, 150 g ofadditional ice was added so as to ensure that, at the conclusion of theaddition, there was still ice remaining in the mixture. Ethyl acetate (1L) was added. Ammonium hydroxide (274 mL) was then added slowly to thestirring biphasic mixture, along with another 750 g of ice, until the pHof the mixture rose to about 8. The mixture was then warmed to about 30°C. to dissolve all of the solids present. The EtOAc was separated andthe aqueous phase was extracted with EtOAc (4×100 mL). The combinedEtOAc extracts were washed with brine, dried over MgSO₄, filtered andconcentrated to provide the title compound. Yield 14.72 g (91%).Recrystaization from EtOH afforded an analytically pure sample, mp 286C.¹H NMR (400 MHz, dmso-d₆) δ 8.86 (s, 1H), 8.16 (s, 1H), 7.90 (d, 1H),7.84 (br. s., 1H), 7.74 (s, 1H), 7.69 (br. s., 1H), 7.43 (d, 1H), 4.91(dd, 1H), 4.54 (dd, 1H), 4.26 (dd, 1H), 4.09 (br. s., 1H), 3.97 (s, 3H),2.63 (m, 1H), 1.60 (m, 2H), 1.02 (t, 3H). ¹⁹F NMR (H decoupled, 376 MHz,dmso-d₆) δ −199.26.

The following compounds of the invention were prepared similarly usingthe methods described above. The reactants A were prepared as describedin this specification. The reactants B were either known compounds thatwere commercially available, or known compounds that were prepared asdescribed in the cited references, or compounds prepared as described inthis specification. For those examples characterized by HPLC retentiontime, the following HPLC conditions were used:

Method PF-AB01 Method PF-AB10 Method PF-CD05 Column Xbridge C18 ColumnXbridge C18 Column Xbridge C18 2.1 × 50 mm 5 μm 2.1 × 50 mm 5 μm 2.1 ×50 mm 5 μm Temperature 50° C. Temperature 50° C. Temperature 50° C.Mobile Phase A Mobile Phase A Mobile Phase A 0.05% 0.0375% TFA in water0.0375% TFA in water NH₄OH in water Mobile Phase B Mobile Phase B MobilePhase B 100% 0.01875% 0.01875% acetonitrile TFA in acetonitrile TFA inacetonitrile Gradient - Initial Gradient - Initial Gradient - Initial 1%B 10% B 5% B Time 0.00 mins 1% B Time 0.00 mins 10% B Time 0.00 mins 5%B Time 0.60 mins 5% B Time 0.50 mins 10% B Time 0.50 mins 5% B Time 4.00mins Time 4.00 mins 100% B Time 3.40 mins 100% B 100% B Time 4.30 mins1% B Time 4.30 mins 10% B Time 4.20 mins 100% B Time 4.70 mins 1% B Time4.70 mins 10% B Time 4.21 mins 5% B Flow rate 0.8 ml/min Flow rate 0.8ml/min Time 4.70 mins 5% B Injection volume 2 μl Injection volume 2 μlFlow rate 0.8 ml/min Injection volume 2 μl Agilent 1200 HPLC/ Agilent1200 HPLC/ Agilent 1200 HPLC/ 1956 MSD/SEDEX 1956 MSD/SEDEX 1956MSD/SEDEX 75 ELSD 75 ELSD 75 ELSD Ionization Mode Ionization ModeIonization Mode API-ES API-ES API-ES Polarity - Positive Polarity -Positive Polarity - Positive

TABLE 1 Reac- Reactant Meth- Ex. Structure tant A B Source ods MH⁺Characterization 1

P4 95849- 02-8 commer- cial 1 316 Rt = 1.752 min; method PF-AB01 2

P4 140695- 84-7 commer- cial 4, 10 344 ¹H NMR (400 MHz, CD₃OD) δ 8.95(d, 1 H), 8.53 (s, 1 H), 7.81 (s, 1 H), 7.52 (d, 1 H), 5.08 (dt, 1 H),4.55-4.64 (m, 1 H), 4.43-4.55 (m, 1 H), 3.65-3.77 (m, 1 H), 3.46 (d, 1H), 2.95-3.10 (m, 2 H), 2.64 (td, 1 H), 2.00-2.20 (m, 2 H), 1.82-2.00(m, 1 H), 1.54-1.69 (m, 1 H), 1.51 (d, 6 H) 3

P4 140695- 85-8 commer- cial 4, 10 344 ¹H NMR (400 MHz, CD₃OD) δ 8.59(d, 1 H), 8.49 (s, 1 H), 7.89 (s, 1 H), 7.65 (s, 1 H), 7.01 (d, 1 H),4.91 (dt, 1 H), 4.18-4.26 (m, 1 H), 4.09-4.18 (m, 1 H), 3.32-3.39 (m, 1H), 3.03-3.13 (m, 1 H), 2.56-2.72 (m, 2 H), 2.18-2.33 (m, 1 H),1.97-2.08 (m, 1 H), 1.77-1.87 (m, 1 H), 1.59-1.72 (m, 1 H), 1.50 (d, 6H), 1.36-1.47 (m, 1 H) 4

P4 123855- 51-6 commer- cial 4, 10 344 ¹H NMR (600 MHz. dmso-d₆) δ8.59-8.60 (d, 1 H), 8.26-8.32 (m, 1 H), 7.72 (br. s., 1 H), 7.68 (br.s., 1 H), 6.98-6.99 (d, 1 H), 4.81-4.85 (dt, 1 H), 4.55 (br. s., 1 H),3.53- 3.55 (d, 2 H), 3.41 (br. t., 2 H), 2.78-2.82 (t, 2 H), 1.88-1.90(d, 2 H), 1.65 (br. s., 1 H), 1.48-1.55 (m, 2 H), 1.45-1.46 (d, 6 H) 5

P4 419572- 18-2 Ref. 1 1, 10 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.60 (d, 1H), 8.21 (s, 1 H), 7.71 (d, 2 H), 7.52 (s, 1 H), 6.99 (d, 1 H), 4.80(quin, 1 H), 4.20 (d, 2 H), 2.87 (d, 2 H), 2.67 (d, 2 H), 1.50 (m, 2 H),1.40 (d, 6 H), 1.30 (m, 1 H) 6

P4 6246- 06-6 commer- cial 1 317 Rt = 2.039 min; method PF-AB01 7

P4 3637- 61-4 commer- cial 1 329 Rt = 2.528 min; method PF-AB10 8

P4 7515- 29-9 commer- cial 1 329 Rt = 2.488 min; method PF-AB10 9

P4 4415- 82-1 commer- cial 1 315 Rt = 2.384 min; method PF-AB10 10

P4 15833- 61-1 commer- cial 1 331 Rt = 2.179 min, method PF-AB01 11

P4 97- 99-4 commer- cial 1 331 Rt = 2.210 min, method PF-AB01 12

P4 3143- 02-0 commer- cial 1 331 Rt = 2.175 min, method PF-AB01 13

P4 38401- 41-1 commer- cial 1 329 Rt = 2.533 min; method PF-AB10 14

P4 497- 36-9 commer- cial 1 341 Rt = 2.501 min; method PF-AB10 15

P4 22415- 59-4 commer- cial 1 331 Rt = 2.213 min; method PF-AB01 16

P4 1632- 68-4 commer- cial 1 341 Rt = 2.496 min; method PF-AB10 17

P4 695- 04-5 Ref. 2 1 339 Rt = 2.404 min; method PF-AB10 18

P4 5464- 28-8 commer- cial 1 333 Rt = 2.097 min; method PF-AB01 19

P4 61277- 90-5 commer- cial 1 341 Rt = 2.507 min; method PF-AB10 20

P2 130658- 13-8 Ref. 3 1, 7, 10 356 ¹H NMR (400 MHz, dmso-d₆) δ 9.07(br. s., 2 H), 8.21 (s, 1 H), 7.90 (d, 1 H), 7.73 (br. s., 2 H), 7.57(s, 1 H), 7.43 (d, 1 H), 5.55 (m, 1 H), 4.92 (dt, 2 H), 3.50 (d, 1 H),3.22 (m, 3 H), 2.90 (m, 2 H), 2.15 (m, 1 H), 2.07 (d, 1 H), 1.87 (m, 1H), 1.67 (br. s., 1 H), 1.39 (m, 4 H) 21

P4 130658- 13-8 Ref. 3 1, 10 356 Rt = 2.363 min; method PF-CD05 22

P4 199174- 24-8 commer- cial 1, 10, 11 397 ¹H NMR (400 MHz, dmso-d₆) δ8.67 (d, 1 H), 8.23 (s, 1 H), 7.72 (br. s, 2 H), 7.51 (d, 1 H), 7.02 (s,1 H), 4.88 (quin, 1 H), 4.23- 4.32 (m, 2 H), 3.95 (d, 2 H), 3.38- 3.78(m, 4 H), 2.79-2.93 (m, 1 H), 2.12-2.23 (m, 1 H), 1.80-2.11 (m 1 H),1.41 (d, 6 H) 23

P4 138108- 72-2 commer- cial 1, 10, 11 397 ¹H NMR (400 MHz, dmso-d₆) δ8.67 (d, 1 H), 8.23 (s, 1 H), 7.72 (br. s, 2 H), 7.51 (d, 1 H), 7.02 (s,1 H), 4.88 (quin, 1 H), 4.23- 4.32 (m, 2 H), 3.95 (d, 2 H), 3.38-3.78(m, 4 H), 2.79-2.93 (m, 1 H), 2.12-2.23 (m, 1 H), 1.80-2.11 (m 1 H),1.41 (d, 6 H) 24

P2 15833- 61-1 commer- cial 1, 7 331 Rt = 2.767 min; method PF-AB01 25

P2 100- 72-1 commer- cial 1, 7 345 Rt = 3.053 min; method PF-AB01 26

P2 17342- 08-4 commer- cial 1, 7 344 ¹H NMR (400 MHz, dmso-d₆) δ 8.19(s, 1 H), 8.11 (s, 1 H), 7.88 (d, 1 H), 7.72 (br. d, 2 H), 7.64 (s, 1H), 7.42 (d, 1 H), 4.91 (m, 1 H), 4.47 (dd, 1 H), 4.31 (dd, 1 H), 4.02(br. s., 1 H), 2.30 (m, 3 H), 1.91 (m, 1 H), 1.39 (d, 6 H) 27

P2 849599- 08-2 Ref. 4 1, 7 394 Rt = 2.598 min; method PF-AB01 28

P2 140695- 84-7 commer- cial 1, 7, 10 344 ¹H NMR (400 MHz, dmso-d₆) δ8.18 (s, 1 H), 7.88 (d, 1 H), 7.72 (br. s, 2 H), 7.55 (s, 1 H), 7.38 (d,1 H), 4.82 (m, 1 H), 4.31 (m, 2 H), 3.32 (br. s., 1 H), 3.07 (m, 1 H),2.85 (d, 1 H), 2.41 (m, 2 H), 2.19 (m, 1 H), 2.01 (m, 1 H), 1.85 (m, 1H), 1.58 (br. s., 1 H), 1.40 (d, 6 H), 1.25 (m, 1 H) 29

P2 1217272- 20-2 Ref. 5 1, 7 360 Rt = 2.458 min; method PF-AB01 30

P2 22415- 59-4 commer- cial 1, 7 331 Rt = 2.809 min; method PF-AB01 31

P2 34381- 71-0 commer- cial 1, 7 344 Rt = 2.184 min; method PF-AB01 32

P2 66673- 40-3 commer- cial 1, 7 344 ¹H NMR (500 MHz, dmso-d₆) δ 8.18(s, 1 H), 8.10 (br. s, 1 H), 7.87 (d, 1 H), 7.76 (br. s., 1 H), 7.70(br. s., 1 H), 7.63 (s, 1 H), 7.41 (d, 1 H), 4.90 (dt, 1 H), 4.46 (dd, 1H), 4.31 (dd, 1 H), 3.98- 4.08 (m, 1 H), 2.15-2.36 (m, 3 H), 1.86-1.95(m, 1 H), 1.40 (d, 3 H), 1.38 (d, 3 H) 33

P2 846057- 27-0 commer- cial 1, 7 386 Rt = 2.626 min; method PF-AB01 34

P2 1428775- 91-0 Ref. 6 1, 7, 10 360 Rt = 2.208 min; method PF-AB01 35

P2 7517-99- 9 commer- cial 1, 7 346 Rt = 2.319 min; method PF-AB01 36

P2 14774- 37-9 commer- cial 1, 7 345 Rt = 2.874 min; method PF-AB01 37

P2 135065- 76-8 commer- cial 1, 7, 10 346 Rt = 2.149 min; method PF-AB0138

P2 614730- 97-1 commer- cial 1, 7, 10 362 Rt = 2.258 min; method PF-AB0139

P2 135065- 69-9 commer- cial 1, 7, 10 346 Rt = 2.145 min; method PF-AB0140

P2 161152- 76-7 Ref. 7 1, 7, 10 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s,1 H), 7.87 (d, 1 H), 7.72 (br. s., 2 H), 7.55 (s, 1 H), 7.38 (d, 1 H),4.81 (dt, 1 H), 4.62 (d, 2 H), 2.95 (d, 1 H), 2.70-2.85 (m, 3 H), 1.40(d, 6 H), 0.68 (d, 2 H), 0.02 (d, 1 H); 41

P2 83435- 58-9 commer- cial 1, 7, 10 330 Rt = 2.132 min; method PF-AB0142

P2 419572- 18-2 Ref. 8 1, 7, 10 342 Rt = 2.211 min; method PF-AB01 43

P2 157634- 00-9 commer- cial 1, 7, 10 344 Rt = 2.227 min; method PF-AB0144

P2 40987- 46-0 Ref. 9 1, 7 360 Rt = 2.156 min; method PF-AB01 45

P2 7583-53- 1 commer- cial 1, 7 358 Rt = 2.259 min; method PF-AB01 46

P2 L122 1, 7, 10 398 Rt = 2.349 min; method PF-AB01 47

P2 135065- 71-3 commer- cial 1, 7, 10 346 Rt = 2.088 min; method PF-AB0148

P2 140695- 85-8 commer- cial 1, 7, 10 344 Rt = 2.216 min; method PF-AB0149

P2 199174- 24-8 commer- cial 1, 7, 10 330 Rt = 2.127 min; method PF-AB0150

P4 199174- 24-8 commer- cial 1, 10 330 Rt = 1.824 min; method PF-AB01 51

P4 135065- 76-8 Commer- cial 1, 10 346 Rt = 1.805 min; method PF-AB01 52

P4 1338247- 76-9 commer- cial 1, 10 370 Rt = 1.963 min; method PF-AB0153

P4 135065- 71-3 commer- cial 1, 10 346 Rt = 1.812 min; method PF-AB01 54

P4 614730- 97-1 commer- cial 1, 10 362 Rt = 1.887 min; method PF-AB01 55

P4 1239999- 37-1 Ref. 10 1, 10 358 Rt = 1.963 min; method PF-AB01 56

P4 236406- 21-6 commer- cial 1, 10 358 Rt = 2.454 min; method PF-CD05 57

P4 97859- 49-9 Ref. 11 1, 10 346 Rt = 1.887 min; method PF-AB01 58

P4 221298- 00-6 commer- cial 1, 10 358 Rt = 1.964 min; method PF-AB01 59

P4 4606-65- 9 commer- cial 1 344 Rt = 2.349 min; method PF-CD05 60

P4 142253- 56-3 commer- cial 1, 10, 11 383 ¹H NMR (400 MHz, dmso-d₆) δ8.66 (d, 1 H), 8.25 (s, 1 H), 7.73 (br. s., 2 H), 7.49 (s, 1 H), 7.07(d, 1 H), 4.81 (dt, 1 H), 4.37- 4.47 (m, 2 H), 4.29-4.37 (m, 1 H), 4.16(dd, 1 H), 4.09 (t, 1 H), 3.93 (dd, 1 H), 3.80 (d, 2 H), 3.19 (td, 1 H),1.40 (d, 2 H), 1.37 (d, 3 H) 61

P2 83435- 58-9 commer- cial 1, 7, 10, 11 397 Rt = 2.637 min; methodPF-AB01 62

P2 123855- 51-6 commer- cial 1, 7, 10, 11 411 Rt = 2.666 min; methodPF-AB01 63

P2 69610- 40-8 commer- cial 1, 7, 10, 11 397 Rt = 2.638 min; methodPF-AB01 64

P2 714971- 28-5 commer- cial 1, 7, 10, 11 413 Rt = 2.522 min; methodPF-AB01 65

P2 168540- 07-6 commer- cial 1, 7, 10, 11 411 Rt = 2.876 min; methodPF-AB01 66

P2 199174- 24-8 commer- cial 1, 7, 10, 11 397 Rt = 2.576 min; methodPF-AB01 67

P2 140695- 85-8 commer- cial 1, 7, 10, 11 411 Rt = 2.755 min; methodPF-AB01 68

P2 1244772- 37-9 Ref. 12 1, 7, 10, 11, chiral HPLC 423 Rt = 2.83 min;method PF-AB01 69

P2 142253- 56-3 commer- cial 1, 7, 10, 11 383 Rt = 2.458 min; methodPF-AB01 70

P2 138108- 72-2 commer- cial 1, 7, 10, 11 397 Rt = 2.577 min; methodPF-AB01 71

P4 130658- 13-8 Ref. 13 1, 10, 11 423 ¹H NMR (400 MHz, dmso-d₆) δ 8.71(d, 2 H), 8.27 (s, 0.5 H, diastereomer 1), 8.25 (s, 0.5 H, diastereomer2), 7.75 (br. s., 2 H), 7.44 (s, 0.5 H, diastereomer 1), 7.32 (s, 0.5 H,diastereomer 1), 7.18 (m, 1 H), 5.10-5.25 (m, 1 H), 4.87 (quin, 0.5 H,diastereomer 1), 4.77 (quin, 0.5 H, diastereomer 2), 4.00 (d, 2 H), 3.82(m, 1 H), 3.65 (m, 1 H), 3.35 (m, 1 H), 3.07- 3.26 (m, 1 H), 2.80-2.97(m, 1 H), 1.83-2.31 (m, 3 H), 1.53-1.70 (m, 1 H), 1.33-1.44 (m, 6H) 72

P2 1279569- 31-1 Ref. 14 1, 7, 10 342 ¹H NMR (400 MHz, dmso-d6) δ 8.21(s, 1 H), 7.91 (d, 1 H), 7.73 (br. s, 2 H), 7.57 (s, 1 H), 7.47 (d, 1H), 5.49 (d, 1 H), 4.90 (dt, 1 H), 3.01-3.12 (m, 1 H), 2.92 (dd, 1 H),2.73-2.80 (m, 1 H), 2.64-2.70 (m, 1 H), 2.53-2.59 (m, 1 H), 2.14-2.23(m, 1 H), 2.00-2.10 (m, 1 H), 1.77-1.86 (m, 1 H), 1.70-1.77 (m, 1 H),1.38 (d, 6 H) 73

P2 161511- 85-9 commer- cial 1, 7, 10, 11 383 Rt = 2.518 min; methodPF-AB01 74

P2 198835- 07-3 Ref. 15 1, 7, 10, 11 409 Rt = 2.615 min; method PF-AB0175

P2 135065- 76-8 commer- cial 1, 7, 10, 11 413 Rt = 2.541 min; methodPF-AB01 76

P2 614730- 97-1 commer- cial 1, 7, 10, 11 429 Rt = 2.726 min; methodPF-AB01 77

P2 161152- 76-7 Ref. 7 1, 7, 10, 11 409 Rt = 2.68 min; method PF-AB01 78

P2 135065- 71-3 commer- cial 1, 7, 10, 11 413 Rt = 2.542 min; methodPF-AB01 79

P2 130658- 13-8 Ref. 13 1, 7, 10, 11 423 Rt = 2.754 min; method PF-AB0180

P2 1441392- 37-5 Ref. 16 1, 7, 10, 11 425 Rt = 2.874 min; method PF-AB0181

P2 1244772- 37-9 Ref. 12 1, 7, 10, 11, chiral HPLC 423 Rt = 2.827 min;method PF-AB01 82

P2 1263506- 20-2 commer- cial 1, 7, 10, 11 411 Rt = 2.709 min; methodPF-AB01 83

P2 215917- 99-0 commer- cial 1, 7, 10, 11 413 Rt = 2.521 min; methodPF-AB01 84

P2 1428775- 91-0 Ref. 6 1, 7, 10, 11 427 Rt = 2.58 min; method PF-AB0185

P2 1349715- 96-3 commer- cial 1, 7, 10, 11 411 Rt = 2.728 min; methodPF-AB01 86

P2 236406- 21-6 commer- cial 1, 7, 10, 11 425 Rt = 2.861 min; methodPF-AB01 87

P4 419572- 18-2 Ref. 1 1, 10, 11 409 Rt = 2.114 min; method PF-AB01 88

P4 1349715- 96-3 commer- cial 1, 10, 11 411 Rt = 2.197 min; methodPF-AB01 89

P4 1244772- 37-9 Ref. 12 1, 10, 11, chiral HPLC 423 Rt = 2.235 min;method PF-CD05 90

P4 161152- 76-7 Ref. 7 1, 10, 11, chiral HPLC 409 Rt = 2.149 min; methodPF-AB01 91

P4 236406- 21-6 commer- cial 1, 10, 11 425 Rt = 2.254 min; methodPF-AB01 92

P4 1244772- 37-9 Ref. 12 1, 10, 11 423 Rt = 2.21 min; method PF-AB01 93

P4 140695- 84-7 commer- cial 1, 10, 11 411 Rt = 2.221 min; methodPF-AB01 94

P4 161152- 76-7 Ref. 7 1, 10, 11 409 Rt = 2.136 min; method PF-AB01 95

P4 614730- 97-1 commer- cial 1, 10, 11 429 Rt = 2.211 min; methodPF-AB01 96

P4 1428775- 91-0 Ref. 6 1, 10, 11 427 Rt = 2.119 min; method PF-AB01 97

P4 140695- 85-8 commer- cial 1, 10, 11 411 Rt = 2.212 min; methodPF-AB01 98

P4 135065- 76-8 commer- cial 1, 10, 11 413 Rt = 2.059 min; methodPF-AB01 99

P4 157634- 00-9 commer- cial 1, 10, 11 411 Rt = 2.163 min; methodPF-AB01 100

P4 123855- 51-6 commer- cial 1, 10, 11 411 Rt = 2.159 min; methodPF-AB01 101

P P2 198835- 07-3 Ref. 15 1, 7, 10 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.18(s, 1 H), 7.83-7.93 (m, 1 H), 7.72 (br. s., 2 H), 7.60 (s, 1 H), 7.38(d, 1 H), 5.35-5.48 (m, 1 H), 4.86 (dt, 1 H), 3.39 (br. s., 1 H), 3.25(d, 1 H), 2.82 (br. s., 1 H), 2.68-2.80 (m, 1 H), 2.12-2.24 (m, 1 H),1.58-1.67 (m, 1 H), 1.50-1.58 (m, 1 H), 1.40 (d, 6 H), 1.26-1.37 (m, 1H) 102

P2 198835- 07-3 Ref. 14 1, 7, 10 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.88 (d, 1 H), 7.73 (br. s., 2 H), 7.62 (s, 1 H), 7.38 (d, 1H), 5.42 (s, 1 H), 4.77- 4.93 (m, 1 H), 3.24 (d, 1 H), 2.81 (br. s., 1H), 2.69 (dd, 1 H), 2.18 (ddd, 1 H), 1.49-1.68 (m, 2 H), 1.41 (d, 6 H),1.29-1.39 (m, 1 H) 103

P2 17342- 08-4 commer- cial 1 326 ¹H NMR (500 MHz, CDCl₃) δ 8.07 (s, 1H), 7.93 (d, 1 H), 7.54 (s, 1 H), 7.22 (d, 1 H), 6.12 (br. s., 1 H),4.83 (dt, 1 H), 4.68 (dd, 1 H), 4.43 (dd, 1 H), 4.22 (dd, 1 H),2.34-2.55 (m, 3 H), 1.95- 2.09 (m, 1 H), 1.49 (dd, 6 H) 104

P2 132682- 23-6 Ref. 17 1, 7 346 ¹H NMR (500 MHz, dmso-d₆) δ 8.15 (s, 1H), 7.95 (br. s, 1 H), 7.84 (d, 1 H), 7.69 (br. s., 1 H), 7.67 (br. s.,1 H), 7.59 (s, 1 H), 7.39 (d, 1 H), 4.84 (quin, 1 H), 4.44-4.47 (m, 1H), 4.43 (d, 1 H), 4.35 (dd, 1 H), 4.28 (dd, 1 H), 4.21 (dq, 1 H), 1.36(d, 3 H), 1.34 (d, 3 H) 105

P2 17342- 08-4 commer- cial 1, 15, 16, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ8.21 (s, 1 H), 8.09 (br. s, 1 H), 7.76 (br. s., 2 H), 7.71 (s, 1 H),7.67 (s, 1 H), 4.92 (dt, 1 H), 4.42 (dd, 1 H), 4.28 (dd, 1 H), 3.98-4.05(m, 1 H), 2.44 (s, 3 H), 2.15-2.35 (m, 3 H), 1.87-1.94 (m, 1 H), 1.40(d, 3 H), 1.38 (d, 3 H) 106

P2 128726- 47-6 commer- cial 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.88 (dd, 1 H), 7.74 (br. s., 1 H), 7.70 (br. s., 2 H), 7.66(s, 1 H), 7.41 (d, 1 H), 4.89 (dt, 1 H), 4.40 (d, 2 H), 3.78- 3.86 (m, 1H), 2.12-2.23 (m, 3 H), 1.91-2.00 (m, 1 H), 1.81-1.90 (m, 2 H),1.61-1.73 (m, 3 H), 1.40 (d, 3 H), 1.38 (d, 3 H) 107

P2 L1 1, 7 358 ¹H NMR (400 MHz, dmso-d₆) δ 8.21 (s, 1 H), 7.88 (d, 1 H),7.74 (br. s, 1 H), 7.71 (br. s, 1 H), 7.69 (s, 1 H), 7.42 (d, 1 H),4.85- 5.00 (m, 1 H), 4.50-4.61 (m, 1 H), 4.16-4.28 (m, 1 H), 3.89-4.04(m, 1 H), 2.30-2.48 (m, 3 H), 1.36- 1.44 (m, 6 H), 1.09-1.13 (m, 3H) 108

P2 207405- 59-2 commer- cial 1, 7, 10, chiral HPLC 342 ¹H NMR (400 MHz,dmso-d₆) δ 8.18 (s, 1 H), 7.88 (d, 1 H), 7.71 (br. s, 2 H), 7.53 (s, 1H), 7.39 (d, 1 H), 5.13-5.19 (m, 1 H), 4.85 (dt, 1 H), 3.60 (br. s, 1H), 2.73-2.79 (m, 1 H), 2.51- 2.55 (m, 2 H), 1.99 (ddd, 1 H), 1.73-1.79(m, 1 H), 1.60-1.68 (m, 1 H), 1.45-1.51 (m, 1 H), 1.38 (dd, 6 H) 109

P2 207405- 59-2 commer- cial 1, 7, 10, chiral HPLC 342 ¹H NMR (400 MHz,dmso-d₆) δ 8.18 (s, 1 H), 7.88 (d, 1 H), 7.71 (br. s., 2 H), 7.52 (s, 1H), 7.37 (d, 1 H), 5.07-5.11 (m, 1 H), 4.85 (dt, 1 H), 3.45 (br. s, 1H), 2.66-2.73 (m, 1 H), 2.42-2.46 (m, 2 H), 1.95 (ddd, 1 H), 1.67- 1.73(m, 1 H), 1.57-1.64 (m, 1 H), 1.40-1.45 (m, 1 H), 1.38 (dd, 6 H) 110

P2 156088- 46-9 Ref. 18 1, 7 372 ¹H NMR (500 MHz, dmso-d₆) δ 8.18 (s, 1H), 8.13 (s, 1 H), 7.88 (d, 1 H), 7.74 (br. s., 1 H), 7.71 (br. s., 1H), 7.69 (s, 1 H), 7.41 (d, 1 H), 4.92 (dt, 1 H), 4.57 (dd, 1 H), 4.21(dd, 1 H), 3.91- 4.06 (m, 1 H), 2.10 (dd, 1 H), 1.74 (dd, 1 H), 1.39 (t,6 H), 1.11 (s, 3H), 1.09 (s, 3 H) 111

P2 64320-89- 4 commer- cial 1, 7 344 ¹H NMR (400 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.88 (d, 1 H), 7.72 (br. s., 2 H), 7.59 (s, 1 H), 7.55 (s, 1H), 7.40 (d, 1 H), 4.87 (dt, 1 H), 4.49 (dd, 1 H), 4.41 (dd, 1 H), 3.50(dd, 1 H), 3.19 (dd, 1 H), 2.88-3.01 (m, 1 H), 2.42 (dd, 1 H), 2.13 (dd,1 H), 1.39 (d, 3 H), 1.38 (d, 3 H) 112

P2 L2 1, 7 362 ¹H NMR (500 MHz, dmso-d₆) δ 8.74 (br. s, 1 H), 8.19 (s, 1H), 7.88 (d, 1 H), 7.74 (br. s., 1 H), 7.71 (br. s., 1 H), 7.57 (s, 1H), 7.43 (d, 1 H), 5.28 (dt, 1 H), 4.91 (dt, 1 H), 4.47 (dd, 1 H), 4.34(dd, 1 H), 4.08-4.19 (m, 1 H), 2.30-2.48 (m, 2 H), 1.41 (d, 3 H), 1.38(d, 3 H) 113

P2 L4 1, 7 372 ¹H NMR (500 MHz, dmso-d₆) δ 8.19 (d, 1 H), 8.16 (s, 1 H,diastereomer 1), 8.07 (s, 1 H, diastereomer 2), 7.88 (d, 1 H), 7.74 (br.s., 1 H), 7.71 (br. s., 1 H), 7.68 (s, 1 H, diastereomer 1), 7.61 (s, 1H, diastereomer 2), 7.41 (d, 1 H), 4.90 (dt, 1 H), 4.57 (dd, 1 H,diastereomer 1), 4.46 (dd, 1 H, diastereomer 2), 4.32 (dd, 1 H,diastereomer 1), 4.20 (dd, 1 H, diastereomer 2), 3.97 (td, 1 H),1.88-2.48 (m, 2 H), 1.66-1.80 (m, 1 H), 1.39 (td, 6 H), 1.24-1.37 (m, 2H), 0.92 (td, 3 H) 114

P6 17342-08- 4 commer- cial 5 343 ¹H NMR (500 MHz, dmso-d₆) δ 8.32 (s, 1H), 8.02 (s, 1 H), 7.71 (br. s., 1 H), 7.63 (br. s., 1 H), 7.60 (s, 1H), 7.51 (d, 1 H), 7.29 (t, 1 H), 6.99 (d, 1 H), 4.91 (quin, 1 H), 4.10(t, 2 H), 4.04 (dd, 1 H), 2.17-2.43 (m, 3 H), 1.97 (br. s., 1 H), 1.41(d, 3 H), 1.39 (d, 3 H) 115

P6 138108- 72-2 commer- cial 5 329 ¹H NMR (500 MHz, dmso-d₆) δ 8.33 (s,1 H), 7.70 (br. s., 1 H), 7.65 (br. s., 1 H), 7.55 (s, 1 H), 7.53 (d, 1H), 7.31 (t, 1 H), 7.02 (d, 1 H), 4.86 (dt, 1 H), 4.19- 4.28 (m, 1 H),4.10-4.19 (m, 1 H), 3.21-3.54 (m,4 H), 3.13 (dd, 1 H), 2.90 (dt, 1 H),2.14- 2.27 (m, 1 H), 1.80-1.93 (m, 1 H), 1.41 (d, 6 H) 116

P2 1073338- 64-3 Ref. 19 1, 7 360 ¹H NMR (500 MHz, dmso-d₆) δ 8.44 (d, 1H), 8.19 (s, 1 H), 7.88 (d, 1 H), 7.74 (br. s., 1 H), 7.70 (br. s., 1H), 7.67 (s, 1 H), 7.42 (d, 1 H), 4.93 (dt, 1 H), 4.48- 4.56 (m, 1 H),4.39-4.48 (m, 1 H), 4.04 (s, 2 H), 3.86-3.96 (m, 3 H), 1.38 (t, 6 H) 117

P2 138108- 72-2 commer- cial 1, 7, 10 330 ¹H NMR (500 MHz, dmso-d₆) δ8.20 (s, 1 H), 7.89 (d, 1 H), 7.73 (br. s., 1 H), 7.71 (br. s., 1 H),7.56 (s, 1 H), 7.42 (d, 1 H), 4.87 (quin, 1 H), 4.48-4.57 (m, 1 H),4.39-4.48 (m, 1 H), 3.35-3.52 (m, 2 H), 3.31 (br. s., 1 H), 3.19-3.27(m, 1 H), 3.07-3.17 (m, 1 H), 2.89 (dt, 1 H), 2.11- 2.23 (m, 1 H),1.78-1.90 (m, 1 H), 1.39 (d, 6 H) 118

P2 L101 Ref. 20 1, 7 398 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s, 1 H), 8.03(br. s, 1 H), 7.90 (d, 1 H), 7.74 (br. s., 1 H), 7.71 (br. s., 1 H),7.69 (s, 1 H), 7.42 (d, 1 H), 4.93 (dt, 1 H), 4.60 (dd, 1 H), 4.40 (dd,1 H), 3.92-4.06 (m, 1 H), 1.98 (d, 1 H), 1.62 (br. s., 2 H), 1.51 (d, 1H), 1.40 (t, 6 H), 1.22 (d, 2 H), 1.10 (d, 2 H), 1.01 (br. s., 2 H) 119

P2 161511- 85-9 commer- cial 1, 7, 10 316 ¹H NMR (400 MHz, dmso-d₆) δ8.93 (br. s, 1 H), 8.22 (s, 1 H), 7.93 (d, 1 H), 7.70 (br. s, 2 H), 7.65(s, 1 H), 7.48 (d, 1 H), 4.80- 4.92 (m, 2 H), 4.68-4.79 (m, 2 H),4.13-3.57 (m, 1 H), 3.82-3.95 (m, 1 H), 1.36-1.45 (m, 6 H), 1.23-1.30(m, 2 H) 120

P13 17342-08- 4 commer- cial 1, 7 356 ¹H NMR (500 MHz, dmso-d₆) δ 8.16(s, 1 H), 8.03 (s, 1 H), 7.88 (d, 1 H), 7.77 (br. s., 1 H), 7.70 (br.s., 1 H), 7.38-7.45 (m, 2 H), 4.93 (quin, 1 H), 4.42 (dd, 1 H), 4.37(dd, 1 H), 3.97-4.07 (m, 1 H), 2.08-2.38 (m, 6 H), 1.90-1.98 (m, 2 H),1.85 (q, 1 H), 1.67-1.80 (m, 1 H) 121

P1 17342- 08-4 commer- cial 1, 7 316 ¹H NMR (500 MHz, dmso-d₆) δ 8.16(s,1 H), 8.13 (br. s, 1 H), 7.89 (d, 1 H), 7.84 (br. s., 1 H), 7.69 (br.s., 1 H), 7.63 (s, 1 H), 7.42 (d, 1 H), 4.49 (dd, 1 H), 4.29 (dd, 1 H),4.01-4.08 (m, 1 H), 3.99 (s, 3 H), 2.14-2.37 (m, 3 H), 1.84-1.96 (m, 1H) 122

P7 17342- 08-4 commer- cial 1, 7 330 ¹H NMR (500 MHz, dmso-d₆) δ 8.17(s, 1 H), 8.12 (s, 1 H), 7.88 (d, 1 H), 7.79 (br. s., 1 H), 7.70 (br.s., 1 H), 7.62 (s, 1 H), 7.41 (d, 1 H), 4.48 (dd, 1 H), 4.26- 4.35 (m, 2H), 4.18-4.25 (m, 1 H), 4.03 (br. s., 1 H), 2.12-2.38 (m, 3 H),1.84-1.94 (m, 1 H), 1.44 (t, 3 H) 123

P2 1445951- 44-9 Ref. 21 1, 7, 10 370 ¹H NMR (500 MHz, dmso-d₆) δ 8.21(s, 1 H), 7.88 (d, 1 H), 7.73 (br. s., 2 H), 7.52 (s, 1 H), 7.43 (d, 1H), 4.84 (dt, 1 H), 4.38- 4.50 (m, 2 H), 3.34-3.49 (m, 2 H), 3.18 (d, 1H), 3.02 (dd, 1 H), 2.62-2.72 (m, 1 H), 1.75-1.95 (m, 4 H), 1.66-1.75(m, 1 H), 1.55-1.64 (m, 1 H), 1.40 (d, 6 H) 124

P2 L1 1, 7, chiral HPLC 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.19 (s, 1 H),8.07 (br. s, 1 H), 7.88 (d, 1 H), 7.73 (br. s., 1 H), 7.71 (br. s., 1H), 7.61 (s, 1 H), 7.41 (d, 1 H), 4.89 (quin, 1 H), 4.45 (dd, 1 H), 4.33(dd, 1 H), 3.91-4.00 (m, 1 H), 2.54- 2.59 (m, 1 H), 2.15-2.27 (m, 1 H),1.88 (dt, 1 H), 1.39 (t, 6 H), 1.09 (d, 3 H) 125

P2 L1 1, 7, chiral HPLC 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.16 (s, 1 H),8.12 (br. s, 1 H), 7.85 (d, 1 H), 7.71 (br. s., 1 H), 7.68 (br. s., 1H), 7.65 (s, 1 H), 7.38 (d, 1 H), 4.88 (quin, 1 H), 4.53 (dd, 1 H), 4.18(dd, 1 H), 3.88-3.99 (m, 1 H), 2.32-2.49 (m, 2 H), 1.39-1.49 (m, 1 H),1.31-1.39 (m, 6 H), 1.08 (d, 3 H) 126

P2 L102 Ref. 22 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.21 (s, 1 H),7.55-8.12 (m, 5 H), 7.42 (d, 1 H), 4.91 (dt, 1 H), 4.24-4.42 (m, 2 H),2.35- 2.47 (m, 1 H), 2.23-2.35 (m, 1 H), 2.10-2.23 (m, 1 H), 1.83- 1.97(m, 1 H) 127

P2 L5 1, 7 388 See Ref. 36. 128

P2 L6 1, 7 380 ¹H NMR (400 MHz, dmso-d₆) δ 9.28 (br. s., 1 H), 8.19 (s,1 H), 7.89 (d, 1 H), 7.72 (br. s., 1 H), 7.70 (br. s., 1 H), 7.62 (s, 1H), 7.44 (d, 1 H), 4.83 (dt, 1 H), 4.57 (dd, 1 H), 4.35 (dd, 1 H), 4.15-4.26 (m, 1 H), 2.76-2.96 (m, 1 H), 2.54-2.71 (m, 1 H), 1.39 (t, 6 H) 129

P18 17342- 08-4 commer- cial 1, 7 352 ¹H NMR (400 MHz, dmso-d₆) δ 8.10(s, 1 H), 8.07 (br. s, 1 H), 8.04 (d, 1 H), 7.96 (s, 2 H), 7.75 (br. s.,1 H), 7.50 (d, 1 H), 7.31 (t, 1 H), 4.52 (dd, 1 H), 4.30 (dd, 1 H),4.00-4.08 (m, 1 H), 2.14- 2.34 (m, 3 H), 1.85-1.96 (m, 1 H) 130

P2 1192180- 58-7 Ref. 23 1, 7, 17 370 ¹H NMR (500 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.81-7.98 (m, 2 H), 7.72 (d, 2 H), 7.41 (d, 1 H), 5.34 (br.s., 1 H), 4.85 (dt, 1 H), 4.05 (d, 1 H), 2.95-3.09 (m, 1 H), 2.43-2.53(m, 1 H), 2.01- 2.25 (m, 2 H), 1.82-2.03 (m, 2 H), 1.49-1.68 (m, 1 H),1.39 (d, 6 H) 131

P2 L7 1, 7 390 ¹H NMR (400 MHz, dmso-d₆) δ 8.77 (s, 1 H), 8.19 (s, 1 H),7.88 (d, 1 H), 7.64-7.79 (m, 3 H), 4.89 (dt, 1 H), 4.58 (dd, 1 H), 4.26(dd, 1 H), 3.93-4.05 (m, 1 H), 2.10-2.26 (m, 1 H), 1.82-1.99 (m, 1 H),1.61-1.80 (m, 1 H), 1.32-1.44 (m, 6 H), 0.89-1.01 (m, 3 H) 132

P2 L8 1, 7 390 ¹H NMR (400 MHz, dmso-d₆) δ 8.87 (s, 1 H), 8.19 (s, 1 H),7.89 (d, 1 H), 7.72 (d, 2 H), 7.66 (s, 1 H), 7.43 (d, 1 H), 4.81-5.02(m, 1 H), 4.59 (dd, 1 H), 4.26 (dd, 1 H), 4.10-4.21 (m, 1 H), 2.31-2.54(m, 1 H), 2.05-2.27 (m, 1 H), 1.86-2.03 (m, 1 H), 1.58-1.83 (m, 1 H),1.24-1.44 (m, 6 H), 0.96 (s, 3 H) 133

P2 L9 1, 7 376 ¹H NMR (500 MHz, dmso-d₆) δ 8.85 (s, 1 H), 8.20 (s, 1 H),7.58- 7.81 (m, 3 H), 7.43 (d, 1 H), 4.92 (quin, 1 H), 4.57 (dd, 1 H),4.29 (dd, 1 H), 4.15 (dd, 1 H), 2.38-2.68 (m, 1 H), 1.96-2.28 (m, 1 H),1.54 (s, 3 H), 1.39 (d, 6 H) 134

P2 L10 1, 7 376 ¹H NMR (500 MHz, dmso-d₆) δ 8.75 (s, 1 H), 8.20 (s, 1H), 7.61- 7.82 (m, 3 H), 7.43 (d, 1 H), 4.90 (dt, 1 H), 4.57 (dd, 1 H),4.28 (dd, 1 H), 3.95-4.09 (m, 1 H), 2.47-2.55 (m, 1 H), 2.19-2.37 (m, 1H), 1.44-1.56 (m, 3 H), 1.39 (t, 6 H) 135

P2 L4 1, 7, chiral HPLC 372 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H),8.08 (s, 1 H), 7.88 (d, 1 H), 7.72 (d, 2 H), 7.61 (s, 1 H), 7.42 (d, 1H), 4.80-5.00 (m, 1 H), 4.46 (dd, 1 H), 4.32 (dd, 1 H), 3.82-4.03 (m, 1H), 2.33-2.56 (m, 2 H), 1.96-2.21 (m, 1 H), 1.94 (d, 1 H), 1.19- 1.35(m, 1 H), 1.38-1.41 (m, 3 H), 1.51-1.82 (m, 1 H), 1.38- 1.41 (m, 6 H),0.91 (t, 3 H) 136

P2 L4 1, 7, chiral HPLC 372 ¹H NMR (400 MHz, dmso-d₆) δ 8.12-8.28 (m, 2H), 7.89 (d, 1 H), 7.63-7.80 (m, 3 H), 7.42 (d, 1 H), 4.91 (dt, 1 H),4.58 (dd, 1 H), 4.20 (dd, 1 H), 3.98 (dd, 1 H), 2.26-2.46 (m, 2 H), 1.75(ddd, 1 H), 1.47-1.60 (m, 1 H), 1.19-1.35 (m, 1 H), 1.38- 1.41 (m, 6 H),0.87-0.99 (m, 3 H) 137

P2 L11 1, 7 402 ¹H NMR (400 MHz, dmso-d₆) δ 8.24 (s, 1 H), 8.20 (s, 1H), 7.89 (d, 1 H), 7.73 (d, 2 H), 7.61 (s, 1 H), 7.42 (d, 1 H), 4.84-4.97 (m, 1 H), 4.41-4.54 (m, 1 H), 4.32 (dd, 1 H), 3.90-4.01 (m, 1 H),2.18-2.30 (m, 1 H), 1.92-2.10 (m, 1 H), 1.32-1.48 (m, 6 H), 1.23 (s, 3H), 1.13 (s, 3 H) 138

P2 53611-47- 5 commer- cial 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.20(s, 1 H), 7.73 (d, 2 H), 7.52 (br. s., 1 H), 7.41 (d, 1 H), 4.87 (dt, 1H), 4.40 (d, 2 H), 3.14- 3.30 (m, 2 H), 2.34-2.48 (m, 2 H), 2.07-2.20(m, 1 H), 1.92- 2.03 (m, 1 H), 1.51-1.65 (m, 1 H), 1.31-1.45 (m, 6 H)139

P2 161152- 76-7 Ref. 7 1, 7, 10 342 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s,1 H), 7.88 (d, 1 H), 7.74 (d, 2 H), 7.58 (s, 1 H), 7.42 (d, 1 H),4.79-4.95 (m, 1 H), 4.52-4.76 (m, 2 H), 3.56 (br. s., 1 H), 3.20-3.38(m, 2 H), 2.51 (s, 1 H), 1.75-1.94 (m, 1 H), 1.40 (d, 6 H), 1.04 (dd, 1H), 0.86 (t, 1 H) 140

P2 161152- 76-7 Ref. 7 1, 7, 10 342 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s,1 H), 7.88 (d, 1 H), 7.74 (d, 2 H), 7.58 (s, 1 H), 7.42 (d, 1 H),4.79-4.92 (m, 1 H), 4.55-4.74 (m, 2 H), 3.56 (br. s., 2 H), 3.23-3.36(m, 2 H), 2.48- 2.53 (m, 1 H), 1.79-1.91 (m, 1 H), 1.40 (d, 6 H), 1.03(dd, 1 H), 0.86 (t, 1 H) 141

P2 L35 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s, 1 H), 8.07 (s, 1H), 7.90 (s, 1 H), 7.73 (d, 2 H), 7.65 (s, 1 H), 7.42 (d, 1 H), 4.91(dt, 1 H), 4.50 (dd, 1 H), 4.36 (dd, 1 H), 3.53-3.66 (m, 1 H), 2.47-2.52 (m, 1 H), 2.26-2.37 (m, 1 H), 1.88 (dd, 1 H), 1.31-1.48 (m, 6 H),1.17 (s, 3 H) 142

P2 146059- 77-0 commer- cial 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.20(s, 1 H), 7.90 (d, 1 H), 7.72 (d, 2 H), 7.57 (s, 1 H), 7.48 (br. s., 1H), 7.41 (d, 1 H), 4.87 (dt, 1 H), 4.45-4.55 (m, 1 H), 4.40 (dd, 1 H),3.11 (t, 1 H), 2.51 (d, 1 H), 2.37 (br. s., 1 H), 2.25 (dd, 2 H),1.84-2.04 (m, 1 H), 1.57-1.73 (m, 1 H), 1.40 (d, 6 H) 143

P2 67838-56- 6 Ref. 24 1, 7 380 ¹H NMR (500 MHz, dmso-d₆) δ 8.21 (s, 1H), 7.89 (d, 1 H), 7.74 (br. s., 1 H), 7.73 (s, 1 H), 7.71 (br. s., 1H), 7.34-7.50 (m, 2 H), 4.92 (dt, 1 H), 4.46 (dd, 1 H), 4.39 (dd, 1 H),4.00-4.09 (m, 1 H), 3.28 (ddd, 1 H), 3.10 (dt, 1 H), 2.50-2.59 (m, 1 H),2.17- 2.27 (m, 1 H), 1.40 (t, 6 H) 144

P2 L2 1, 7, chiral HPLC 1, 7 362 ¹H NMR (500 MHz, dmso-d₆) δ 8.74 (s, 1H), 8.21 (s, 1 H), 7.89 (d, 1 H), 7.73 (d, 2 H), 7.59 (s, 1 H), 7.44 (d,1 H), 5.15-5.43 (m, 1 H), 4.92 (dt, 1 H), 4.49 (dd, 1 H), 4.35 (dd, 1H), 4.15 (d, 1 H), 2.48-2.64 (m, 1 H), 2.23-2.46 (m, 1 H), 1.30-1.58 (m,6 H) 145

P2 L2 1, 7, chiral HPLC 1, 7 362 ¹H NMR (500 MHz, dmso-d₆) δ 8.71 (s, 1H), 8.20 (s, 1 H), 7.89 (d, 1 H), 7.74 (br. s., 3 H), 7.43 (d, 1 H),5.01-5.27 (m, 1 H), 4.88 (dt, 1 H), 4.59 (dd, 1 H), 4.29 (dd, 1 H), 4.04(br. s., 1 H), 2.62-2.84 (m, 1 H), 1.97-2.21 (m, 1 H), 1.39 (t, 6 H) 146

P1 L6 Ref. 25 2, 7 352 ¹H NMR (500 MHz, dmso-d₆) δ 9.29 (br. s., 1 H),8.12 (s, 1 H), 7.85 (d, 1 H), 7.82 (br. s., 1 H), 7.60-7.71 (m, 1 H),7.56 (s, 1 H), 7.39 (d, 1 H), 4.55 (dd, 1 H), 4.29 (dd, 1 H), 4.10-4.22(m, 1 H), 3.91 (s, 3 H), 2.75- 2.95 (m, 1 H), 2.51-2.66 (m, 1 H) 147

P2 89531-65- 7 Ref. 26 1, 7 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1H), 7.97 (s, 1 H), 7.88 (d, 1 H), 7.72 (d, 2 H), 7.64 (s, 1 H), 7.41 (d,1 H), 5.03 (t, 1 H), 4.91 (dt, 1 H), 4.38-4.49 (m, 1 H), 4.28-4.38 (m, 1H), 3.54-3.66 (m, 1 H), 3.43-3.53 (m, 1 H), 2.21-2.38 (m, 2 H), 1.85-2.12 (m, 2 H), 1.33-1.50 (m, 6 H) 148

P2 L12 2, 7, 9 374 ¹H NMR (500 MHz, dmso-d₆) δ 8.18 (s,1 H), 8.10 (br.s, 1 H), 7.87 (d, 1 H), 7.75 (br. s., 1 H), 7.70 (s, 1 H), 7.61 (br. s,1 H), 7.40 (d, 1 H), 4.90-4.98 (m, 1 H), 4.43-4.48 (m, 2 H), 4.29- 4.36(m, 1 H), 4.23 (dd, 1 H), 3.96-4.02 (m, 1 H), 2.52-2.63 (m, 1 H),2.15-2.29 (m, 1 H), 1.95-2.08 (m, 1 H), 1.39 (t, 6 H) 149

P2 203982- 57-4 Ref. 27 2, 7, 9 359 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s,1 H), 8.05 (s, 1 H), 7.89 (d, 1 H), 7.74 (br. s., 1 H), 7.72 (br. s., 1H), 7.65 (s, 1 H), 7.42 (d, 1 H), 4.92 (dt, 1 H), 4.58 (dd, 1 H), 4.32(dd, 1 H), 3.58-3.65 (m, 1 H), 3.44-3.50 (m, 1 H), 1.97 (dd, 1 H), 1.36-1.44 (m, 7 H) 150

P2 L13 1, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.28 (s, 1 H), 8.12-8.24 (m,1 H), 7.88 (d, 1 H), 7.64-7.82 (m, 3 H), 7.41 (d, 1 H), 5.55 (d, 1 H),4.95 (quin, 1 H), 4.56 (dd, 1 H), 4.22 (dd, 1 H), 4.13 (td, 1 H), 3.90(qd, 1 H), 2.52-2.57 (m, 1 H), 1.67 (dt, 1 H), 1.29- 1.47 (m, 6 H) 151

P2 L15 2, 7, HPLC 426 ¹H NMR (400 MHz, dmso-d₆) δ 8.30 (s, 1 H), 8.11(s, 1 H), 7.80- 7.82 (d, 2 H), 7.47 (s, 1 H), 7.34-7.36 (d, 1 H),4.74-4.77 (m, 1 H), 4.39-4.40 (m, 1 H), 4.32-4.34 (m, 1 H), 3.93-3.98(m, 1 H), 2.59-2.75 (m, 3 H), 2.18-2.31 (m, 3 H), 1.29-1.33 (m, 6 H).152

P2 L16 2, 7, HPLC 426 ¹H NMR (400 MHz, dmso-d₆) δ 8.44 (s, 1 H), 8.11(s, 1 H), 7.80- 7.81 (d, 1 H), 7.61-7.66 (m, 3 H), 7.33-7.35 (d, 1 H),4.83- 4.86 (m, 1 H), 4.49-4.52 (m, 1 H), 4.14-4.18 (m, 1 H), 3.96 (s, 1H), 2.59-2.66 (m, 3 H), 2.25-2.28 (m, 1 H), 1.61-1.64 (m, 1 H),1.29-1.33 (m, 6 H). 153

P2 69531-65- 7 Ref. 26 1, 7, HPLC 374 ¹H NMR (500 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.97 (s, 1 H), 7.88 (d, 1 H), 7.68-7.79 (m, 2 H), 7.63 (s, 1H), 7.41 (d, 1 H), 5.11 (t, 1 H), 4.91 (dt, 1 H), 4.40-4.49 (m, 1 H),4.30-4.39 (m, 1 H), 3.49-3.62 (m, 2 H), 2.23-2.39 (m, 2 H), 2.01-2.13(m, 1 H), 1.90-2.01 (m, 1 H), 1.33-1.44 (m, 6 H) 154

P2 89531-65- 7 Ref. 26 1, 7, HPLC 374 ¹H NMR (500 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.97 (s, 1 H), 7.88 (d, 1 H), 7.70-7.80 (m, 2 H), 7.41 (d, 1H), 5.11 (t, 1 H), 4.91 (dt, 1 H), 4.40-4.47 (m, 1 H), 4.32-4.40 (m, 1H), 3.49-3.63 (m, 2 H), 2.24-2.41 (m, 2 H), 2.02-2.13 (m, 1 H),1.90-2.02 (m, 1 H), 1.32-1.44 (m, 6 H) 155

P2 L104 1, 7, HPLC 412 ¹H NMR (500 MHz, dmso-d₆) δ 8.40 (s, 1 H), 8.21(s, 1 H), 7.90 (d, 1 H), 7.73 (d, 2 H), 7.61 (s, 1 H), 7.45 (d, 1 H),4.87 (dt, 1 H), 4.48 (dd, 2 H), 4.07-4.20 (m, 2 H), 2.79 (dd, 1 H), 2.34(dd, 1 H), 1.42 (d, 6 H) 156

P2 1315057- 77-2 Ref. 28 1, 7, HPLC 358 ¹H NMR (500 MHz, dmso-d₆) δ8.08-8.24 (m, 2 H), 7.88 (d, 1 H), 7.64-7.78 (m, 2 H), 7.55 (s, 1 H),7.39 (d, 1 H), 5.29 (dd, 1 H), 4.83 (dt, 1 H), 4.14 (t, 1 H), 3.73-3.93(m, 1 H), 1.95-2.30 (m, 3 H), 1.74-1.93 (m, 1 H), 1.31-1.46 (m, 9 H) 157

P2 1315057- 77-2 Ref. 28 1, 7, HPLC 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.18(s, 1 H), 7.93-8.03 (m, 1 H), 7.89 (d, 1 H), 7.60 (s, 1 H), 7.39 (d, 1H), 5.38 (dd, 1 H), 4.90 (dt, 1 H), 3.81-3.95 (m, 1 H), 3.42-3.54 (m, 1H), 2.04- 2.38 (m, 4 H), 1.30-1.48 (m, 9 H) 158

P2 714971- 28-5 commer- cial 346 Rt = min 2.159; method PF-AB01 159

P2 170491- 63-1 commer- cial 330 Rt = min 2.200; method PF-AB01 160

P2 215917- 99-0 commer- cial 346 Rt = min 2.160; method PF-AB01 161

P2 L105 1, 7, 9, 18, HPLC, 10 356 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s, 1H), 7.87 (d, 1 H), 7.74 (br. s., 1 H), 7.72 (br. s., 1 H), 7.61 (s, 1H), 7.41 (d, 1 H), 4.88 (dt, 1 H), 4.48 (d, 1 H), 4.23 (d, 1 H), 3.64(d, 1 H), 3.31 (d, 1 H), 2.90-3.00 (m, 1 H), 2.73- 2.86 (m, 1 H),2.12-2.22 (m, 1 H), 1.79-1.90 (m, 1 H), 1.40 (d, 6 H), 1.30-1.38 (m, 2H), 0.99 (dd, 1 H), 0.86 (t, 1 H) 162

P2 L105 1, 7, 9, 18, HPLC, 10 356 ¹H NMR (500 MHz, dmso-d₆) δ 8.54 (br.s, 1 H), 8.20 (s, 1 H), 7.87 (d, 1 H), 7.74 (br. s., 1 H), 7.72 (br. s.,1 H), 7.61 (s, 1 H), 7.41 (d, 1 H), 4.88 (dt, 1 H), 4.49 (d, 1 H), 4.23(d, 1 H), 3.64 (d, 1 H), 3.31 (d, 1 H), 2.90- 3.03 (m, 1 H), 2.72-2.85(m, 1 H), 2.07-2.25 (m, 1 H), 1.78-1.93 (m, 1 H), 1.40 (d, 6 H), 1.30-1.38 (m, 1 H), 0.99 (dd, 1 H), 0.85 (t, 1 H) 163

P2 L17 2, 7, 9 392 ¹H NMR (500 MHz, dmso-d₆) δ 8.90 (s, 1 H), 8.20 (s, 1H), 7.89 (d, 1 H), 7.59-7.80 (m, 3 H), 7.43 (d, 1 H), 4.95 (dt, 1 H),4.57 (dd, 1 H), 4.27 (dd, 1 H), 4.07-4.22 (m, 1 H), 3.69-3.72 (m, 1 H),3.35 (d, 1 H), 2.29- 2.54 (m, 3 H), 1.26-1.48 (m, 6 H) 164

P2 L18 2, 7, 9 392 ¹H NMR (500 MHz, dmso-d₆) δ 8.75 (s, 1 H), 8.20 (s, 1H), 7.89 (d, 1 H), 7.74 (br. s., 3 H), 7.43 (d, 1 H), 4.88 (dt, 1 H),4.59 (dd, 1 H), 4.29 (dd, 1 H), 4.00 (br. s., 1 H), 3.57-3.73 (m, 2 H),2.77 (ddd, 1 H), 2.05-2.31 (m, 1 H), 1.39 (t, 6 H) 165

P2 L12 2, 7, 9, HPLC 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.22 (s, 1 H), 8.19(s, 1 H), 7.88 (d, 1 H), 7.73 (br. s., 1 H), 7.71 (s, 1 H), 7.70 (br.s., 1 H), 7.41 (d, 1 H), 4.95 (dt, 1 H), 4.71 (t, 1 H), 4.54 (dd, 1 H),4.23 (dd, 1 H), 3.95-4.04 (m, 1 H), 3.55-3.63 (m, 2 H), 2.27-2.38 (m, 1H), 1.78-1.89 (m, 1 H), 1.39 (dd, 6 H) 166

P2 L12 2, 7, 9, HPLC 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 8.11(s, 1 H), 7.88 (d, 1 H), 7.73 (br. s., 1 H), 7.71 (br. s., 1 H), 7.62(s, 1 H), 7.42 (d, 1 H), 4.90 (dt, 1 H), 4.70 (t, 1 H), 4.46 (dd, 1 H),4.32 (dd, 1 H), 3.91-4.01 (m, 1 H), 3.59 (t, 2 H), 2.24 (dt, 1 H), 1.96-2.10 (m, 1 H), 1.39 (t, 6 H) 167

P2 254441- 91-3 Ref. 29 1, 7 416 ¹H NMR (500 MHz, dmso-d₆) δ 8.30 (s, 1H), 7.90 (d, 1 H), 7.73 (d, 2 H), 7.39-7.59 (m, 2 H), 4.88 (dt, 1 H),4.80 (d, 1 H), 4.68 (d, 1 H), 4.50-4.59 (m, 1 H), 4.37-4.50 (m, 1 H),4.00 (t, 1 H), 1.24-1.51 (m, 12 H) 168

special case 17342- 08-4 commer- cial 1, 7, 12, HPLC 362 ¹H NMR (500MHz, dmso-d₆) δ 8.21 (s, 1 H), 8.11 (s, 1 H), 7.75- 7.92 (m, 3 H),7.63-7.72 (m, 1 H), 4.96 (dt, 1 H), 4.46 (dd, 1 H), 4.28 (dd, 1 H),3.96-4.12 (m, 1 H), 2.14-2.36 (m, 3 H), 1.85-1.97 (m, 1 H, ), 1.34-1.47(m, 6 H) 169

P2 17342- 08-4 commer- cial 1, 7, 19, HPLC 345 ¹H NMR (400 MHz, dmso-d₆)δ 13.10 (br. s, 1 H), 8.00-8.21 (m, 2 H), 7.89 (d, 1 H), 7.65 (s, 1 H),7.40 (d, 1 H), 4.85 (dt, 1 H), 4.47 (dd, 1 H), 4.30 (dd, 1 H), 3.89-4.14(m, 1 H), 2.11- 2.37 (m, 3 H), 1.79-2.01 m, 1 H), 1.20-1.47 (m, 6 H) 170

P2 L37 2, 7, HPLC 376 ¹H NMR (500 MHz, dmso-d₆) δ 8.60 (br. s, 1 H),8.21 (s, 1 H), 7.91 (d, 1 H), 7.73 (d, 2 H), 7.39-7.53 (m, 2 H),4.93-5.14 (m, 1 H), 4.79-4.92 (m, 1 H), 4.41-4.57 (m, 2 H), 4.00 (br. s,1 H), 2.68-2.86 (m, 1 H), 1.41 (dd, 6 H), 1.21 (d, 3 H) 171

P2 L19 1, 7, HPLC 420 ¹H NMR (400 MHz, dmso-d₆) δ 8.70 (br. s., 1 H),8.17 (s, 1 H), 7.88 (d, 1 H), 7.72 (m, 3 H), 7.41 (d, 1 H), 4.98 (s, 1H), 4.87- 4.91 (m, 1 H), 4.55 (d, 1 H), 4.23 (dd, 1 H), 3.92-3.95 (m, 1H), 2.82-2.93 (m, 1 H), 1.88- 2.05 (m, 1 H), 1.38 (m, 6 H), 1.02 (s, 3H), 0.93 (s, 3 H) 173

P5 17342- 08-4 commer- cial 5, 13, 14 315 ¹H NMR (500 MHz, dmso-d₆) δ8.29 (s, 1 H), 8.07 (s, 1 H), 7.80 (br. s, 1 H), 7.57-7.70 (m, 2 H),7.53 (d, 1 H), 7.32 (t, 1 H), 7.01 (d, 1 H), 4.02-4.20 (m, 2 H), 4.00(s, 3 H), 3.92-4.02 (m, 1 H), 2.12-2.46 (m, 3 H, ), 1.86- 2.06 (m, 1 H)174

P2 L72 3, 7 356 ¹H NMR (400 MHz, dmso-d₆) δ 8.21 (s, 1 H), 7.90 (d, 1H), 7.73 (d, 2 H), 7.65 (s, 1 H), 7.59 (s, 1 H), 7.43 (d, 1 H), 4.92(dt, 1 H), 4.45-4.60 (m, 1 H), 4.33- 4.45 (m, 1 H), 3.88 (t, 1 H),1.92-2.12 (m, 1 H), 1.76 (br. s, 1 H), 1.42 (t, 6 H), 1.10 (td, 1 H),0.60 (q, 1 H) 175

P2 L100 Ref. 7 1, 7 356 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 7.88(d, 1 H), 7.72 (br. s., 1 H), 7.70 (br. s., 1 H), 7.56 (s, 1 H), 7.41(d, 1 H), 7.20 (br. s, 1 H), 4.84 (dt, 1 H), 4.67 (d, 1 H), 4.60 (d, 1H), 3.54 (d, 1 H), 3.39 (d, 1 H), 1.77-1.89 (m, 1 H), 1.40 (d, 6 H),1.36 (dd, 1 H), 0.84 (t, 1 H) 176

P2 17342- 08-4 commer- cial 1, 7, 12, HPLC 362 ¹H NMR (500 MHz, dmso-d₆)δ 7.98 (d, 1 H), 7.81-7.93 (m, 2 H), 7.77 (s, 2 H), 7.47 (dd, 1 H),4.32-4.56 (m, 3 H), 3.90-4.08 (m, 1 H), 2.09-2.44 (m, 3 H), 1.91-2.05(m, 1 H), 1.30 (dd, 6 H) 177

P1 L10 2, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 9.00 (s, 1 H), 8.35 (s, 1H), 8.04- 8.10 (m, 3 H), 7.89 (s, 2 H), 7.62-7.63 (d, 1 H), 4.76-4.790(m, 1 H), 4.43-4.47 (m, 1 H), 4.18-4.26 (m, 1 H), 4.17 (s, 3 H),2.64-2.75 (m, 1 H), 2.42- 2.52 (m, 1 H), 1.65-1.71 (m, 3 H) 178

P19 17342- 08-4 commer- cial 1, 20, 7 370 ¹H NMR (500 MHz, dmso-d₆) δ8.24 (s, 1 H), 8.16-8.21 (m, 2 H), 8.12 (d, 2 H), 7.79 (s, 1 H), 7.55(d, 1 H), 4.54 (dd, 1 H), 4.30 (dd, 1 H), 3.94-4.12 (m, 1 H), 2.13-2.34(m, 3 H), 1.81- 1.99 (m, 1 H) 179

P2 L14 1, 7, HPLC 360 ¹H NMR (500 MHz, dmso-d₆) δ 8.21 (br. s, 1 H),8.19 (s, 1 H), 7.88 (d, 1 H), 7.73 (br. s., 1 H), 7.70 (br. s., 1 H),7.60 (s, 1 H), 7.41 (d, 1 H), 4.89 (dt, 1 H), 4.45 (dd, 1 H), 4.31 (dd,1 H), 4.27 (t, 1 H), 3.94-4.04 (m, 1 H), 2.30 (ddd, 1 H), 2.04 (dt, 1H), 1.40 (dd, 7H) 180

P2 122663- 19-8 Ref. 30 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s, 1H), 7.90 (d, 1 H), 7.72 (br. s, 2 H), 7.46 (s, 1 H), 7.43 (d, 1 H), 4.80(dt, 1 H), 4.72 (dd, 1 H), 4.49 (dd, 1 H), 3.88-4.14 (m, 1 H), 2.81 (s,3 H), 2.35- 2.47 (m, 1 H), 2.18-2.35 (m, 2 H), 1.86-2.10 (m, 1 H), 1.41(d, 6 H) 181

P2 L20 1, 7 444 ¹H NMR (400 400 MHz, dmso-d₆) δ 8.13-8.25 (m, 2 H),7.83-7.97 (m, 1 H), 7.67-7.77 (m, 2 H), 7.56- 7.68 (m, 1 H), 7.42 (dd, 1H), 4.78-5.02 (m, 1 H), 4.40- 4.52 (m, 1 H), 4.26-4.40 (m, 1 H), 3.94(d, 1 H), 3.65 (d, 3 H), 2.53-2.64 (m, 1 H), 2.10- 2.42 (m, 2 H),1.84-2.10 (m, 2 H), 1.58-1.83 (m, 2 H), 1.33- 1.46 (m, 6 H), 1.17-1.33(m, 1 H) 182

P2 L21 2, 7, HPLC 442 ¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1 H), 7.86-7.88(m, 2 H), 7.34-7.35 (d, 1 H), 5.00-5.06 (m, 1 H), 4.63-4.67 (m, 1 H),4.46-4.50 (m, 1 H), 4.12-4.16 (m, 1 H), 3.66-3.67 (m, 1 H), 2.69-2.78(m, 2 H), 2.57-2.63 (m, 1 H), 2.22-2.27 (m, 1 H), 1.41-1.50 (m, 6 H) 183

P2 L39 2, 7 394 ¹H NMR (400 MHz, dmso-d₆) δ 9.32 (s, 1 H), 8.24 (s, 1H), 7.95- 7.94 (d, 1 H), 7.77 (s, 2 H), 7.66 (s, 1 H), 7.50-7.48 (d, 1H), 4.87-4.85 (m, 1 H), 4.61-4.58 (m, 1 H), 4.42-4.41 (m, 1 H), 4.20 (s,1 H), 3.09-3.04 (m, 1 H), 1.44-1.43 (d, 6 H), 1.23- 1.21 (d, 3 H). 184

P2 L21 2, 7, HPLC 442 ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1 H), 7.78-7.80(d, 1 H), 7.67 (s, 1H), 7.24-7.26 (d, 1 H), 4.86-4.91 (m, 1 H), 4.57-4.6 (m, 1 H), 4.29-4.33 (m, 2 H), 2.67-2.73 (m, 1 H), 2.33- 2.47 (m, 2H), 2.13-2.19 (m, 1 H), 1.37-1.39 (m, 6 H). 185

P2 L106 7, 2 359 ¹H NMR (500 MHz, dmso-d₆) δ 8.18 (s, 1 H), 7.87 (d, 1H), 7.76 (br. s, 1 H), 7.68 (br. s, 1 H), 7.62 (s, 1 H), 7.41 (d, 1 H),4.91 (dt, 1 H), 4.45 (dd, 1 H), 4.32 (dd, 1 H), 4.03 (dd, 1 H), 3.47-3.58 (m, 1 H), 3.28 (dd, 1 H), 2.68 (s, 3 H), 1.31-1.45 (m, 6 H) 186

P2 L107 7, 2, 9 384 ¹H NMR (500 MHz, dmso-d₆) δ 8.19 (s, 1 H), 7.86 -7.91 (m, 2 H), 7.71 (br. s., 2 H), 7.49 (s, 1 H), 7.40 (d, 1 H), 5.29(t, 1 H), 4.80 (quin, 1 H), 2.52-2.60 (m, 1 H), 2.22-2.38 (m, 3 H),1.79- 1.96 (m, 3 H), 1.70-1.79 (m, 2 H), 1.60-1.71 (m, 1 H), 1.40 (dd, 6H) 187

P2 L38 2, 7 376 ¹H NMR (400 MHz, dmso-d₆) δ 8.72 (s, 1 H), 8.18 (s, 1H), 7.84- 8.01 (m, 1 H), 7.63-7.84 (m, 3 H), 7.42 (d, 1 H), 4.80-5.10(m, 2 H), 4.55 (dd, 1 H), 4.30 (dd, 1 H), 4.04 (m, 1 H), 1.31- 1.44 (m,6 H), 1.09 (d, 3 H) 188

P1 L37 2, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 8.65 (s, 1 H), 8.12-8.23 (m,1 H), 7.92 (d, 1 H), 7.84 (s, 1 H), 7.71 (br. s, 1 H), 7.29-7.53 (m, 2H), 4.91-5.21 (m, 1 H), 4.47 (s, 2 H), 3.89-4.11 (m, 4 H), 2.65-2.86 (m,1 H), 1.03-1.28 (m, 3 H) 189

P1 L38 3, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 8.78 (s, 1 H), 8.61-8.90 (m,1 H), 8.12-8.13 (m, 1 H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.71 (br.s., 2 H), 7.45 (d, 1 H), 4.78-5.13 (m, 1 H), 4.58 (dd, 1 H), 4.30 (dd, 1H), 4.03-4.11 (m, 1 H), 3.99 (s, 3 H), 2.75-3.03 (m, 1 H), 1.11 (dd, 3H)190

P2 17342- 08-4 commer- cial 1, 7, 15, 20 369 ¹H NMR (500 MHz, dmso-d₆) δ8.56 (s, 1 H), 8.13-8.25 (m, 2 H), 7.80-7.98 (m, 2 H), 7.76 (s, 1 H),4.99 (dt, 1 H), 4.59 (dd, 1 H), 4.41 (dd, 1 H), 4.07 (d, 1 H), 2.14-2.39(m, 4 H), 1.79- 2.00 (m, 1 H), 1.42 (dd, 6 H) 191

P2 644971- 22-2 commer- cial 1, 7, 10 330 Rt = 2.175 min; method PF-AB01192

P2 L22 2, 7 416 ¹H NMR (500 MHz, dmso-d₆) δ 8.31 (s, 1 H), 8.14-8.22 (m,1 H), 7.88 (d, 1 H), 7.66-7.79 (m, 3 H), 7.41 (d, 1 H), 5.96 (s, 1 H),4.98 (dt, 1 H), 4.84 (d, 1 H), 4.40-4.62 (m, 4 H), 4.25 (dd, 1 H), 4.00(dd, 1 H), 2.96-3.11 (m, 1 H), 2.29-2.43 (m, 1 H), 1.65-1.83 (m, 1 H),1.31-1.46 (m, 6 H) 193

P2 L22 2, 7 416 ¹H NMR (500 MHz, dmso-d₆) δ 8.21 (s, 1 H), 8.15 (s, 1H), 7.90 (d, 1 H), 7.73 (d, 2 H), 7.65 (s, 1 H), 7.43 (d, 1 H), 5.96 (s,1 H), 4.93 (dt, 1 H), 4.83 (d, 1 H), 4.54 (d, 1 H), 4.40-4.52 (m, 3 H),4.32 (dd, 1 H), 3.96 (d, 1 H), 3.11 (t, 1 H), 2.01-2.24 (m, 2 H), 1.40(dd, 6 H) 194

P5 L10 5, 13, 14 347 ¹H NMR (500 MHz, dmso-d₆) δ 8.75 (s, 1 H), 8.29 (s,1 H), 7.79 (br. s., 1 H), 7.69 (s, 1 H), 7.62 (br. s., 1 H), 7.54 (d, 1H), 7.31 (t, 1 H), 7.01 (d, 1 H), 4.16-4.31 (m, 1 H), 3.93-4.09 (m, 5H), 2.23-2.40 (m, 1 H), 1.36-1.59 (m, 3 H) 195

P2 17342- 08-4 commer- cial 1, 7, 15, 20, 9 373 ¹H NMR (500 MHz,dmso-d₆) δ 8.35 (s, 1 H), 8.11 (s, 1 H), 7.92 (s, 1 H), 7.63-7.83 (m, 3H), 4.93 (dt, 1 H), 4.48 (dd, 1 H), 4.33 (dd, 1 H), 4.22 (br. s., 2 H),4.04 (br. s., 2 H), 2.17-2.35 (m, 3 H), 1.85-1.99 (m, 1 H), 1.33-1.48(m, 6 H) 196

378 ¹H NMR (600 MHz, dmso-d6) δ 8.85 (s, 1H), 8.17 (s, 1H), 7.91 (d,1H), 7.85 (br. s, 1H), 7.71 (s, 2H), 7.45 (d, 1H), 4.58 (dd, 1H), 4.48(d, 1H), 4.30 (dd, 1H), 3.98 (s, 3H), 3.87 (dd, 1H), 1.72 (q, 2H), 1.01(t, 3H). 197

378 Major Diastereomer: ¹H NMR (600 MHz, dmso-d6) δ 9.25 (s, 1H), 8.18(s, 1H), 7.92 (d, 1H), 7.6 (s, 1H), 7.72 (s, 1H), 7.6 (s, 1H), 7.54 (s,1H), 4.96 (dd, 1H ), 4.5 (dd, 2H), 3.98 (s, 3H), 2.47 (m, 1H), 1.67 (m,1H), 0.99 (t, 3H). Minor Diastereomer: ¹H NMR (600 MHz, dmso-d6) δ 9.18(s, 1H), 8.16 (s, 1H), 7.91 (d, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.69(s, 1H), 7.44 (s, 1H), 5.14 (dd, 1H ), 4.5 (dd, 2H), 3.92 (s, 3H), 2.39(m, 1H), 1.58 (m, 1H), 0.99 (t, 3H). 198

378 ¹H NMR (600 MHz, dmso-d6) δ 9.0 (s, 1H), 8.17 (s, 1H), 7.91 (d, J1H), 7.86 (br s, 1H), 7.76 (s, 1H), 7.71 (bs, 1H), 7.44 (d, 1H), 4.94(d, 1H), 4.83 (dd, 1H), 4.60 (dd, 1H), 4.26 (dd, 1H), 4.07 (m, 1H), 3.99(m, 1H), 3.916 (m, 1H), 2.56 (m, 1H), 1.23 (d, 3H). 199

P14 17342- 08-4 commer- cial 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ8.01-8.25 (m, 2 H), 7.92 (d, 1 H), 7.86 (br. s., 1 H), 7.74 (br. s., 1H), 7.44 (d, 1 H), 7.14 (s, 1 H), 5.52 (quin, 1 H), 4.91- 5.18 (m, 2 H),4.72 (dd, 1 H), 4.65 (dd, 1 H), 4.38-4.48 (m, 1 H), 4.34 (dd, 1 H),3.94-4.13 (m, 1 H), 2.10-2.41 (m, 3 H), 1.84-2.00 (m, 1 H) 200

P12 17342- 08-4 commer- cial 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.15(s, 1 H), 8.01 (s, 1 H), 7.93 (d, 1 H), 7.79 (s, 1 H), 7.71 (br. s., 2H), 7.44 (d, 1 H), 4.32- 4.47 (m, 2 H), 3.95-4.10 (m, 1 H), 2.11-2.39(m, 3 H), 1.89- 2.05 (m, 1 H), 1.44 (s, 9 H) 201

P2 L40 2, 7 408 ¹H NMR (400 MHz, dmso-d₆) δ 9.32 (s, 1 H), 8.24 (s, 1H), 7.94- 7.96 (d, 1 H), 7.77 (s, 2 H), 7.66 (s, 1 H), 7.49-7.50 (d, 1H), 4.85-4.87 (m, 1 H), 4.59-4.61 (m, 1 H), 4.40-4.43 (m, 1 H), 4.20 (s,1 H), 3.04-3.09 (m, 1 H), 1.43-1.44 (d, 6 H), 1.22- 1.23 (m, 3 H) 202

P2 L108 7, 1 345 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s, 1 H), 7.88 (d, 1H), 7.63- 7.82 (m, 3 H), 7.41 (d, 1 H), 6.76 (s, 1 H), 6.26 (s, 1 H),4.95 (dt, 1 H), 4.45 (dd, 1 H), 4.33 (dd, 1 H), 4.11 (dq, 1 H), 3.56 (t,1 H), 3.25 (dd, 1 H), 1.32-1.44 (m, 6 H) 203

P1 L90 2, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 8.71 (s, 1 H), 8.17 (s, 1H), 7.91 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (br. s., 1 H), 7.65 (s, 1H), 7.45 (d, 1 H), 4.75-4.99 (m, 1 H), 4.66 (dd, 1 H), 4.35 (dd, 1 H),3.97 (s, 3 H), 3.62 (dt, 1 H), 2.27-2.46 (m, 1 H), 1.28 (d, 3 H) 204

P11 17342- 08-4 commer- cial 1, 7 356 ¹H NMR (500 MHz, dmso-d₆) δ8.08-8.29 (m, 2 H), 7.80-7.95 (m, 2 H), 7.77 (br. s., 1 H), 7.62 (s, 1H), 7.43 (d, 1 H), 4.49 (dd, 1 H), 4.28 (dd, 1 H), 4.09-4.21 (m, 1 H),3.92-4.09 (m, 2 H), 2.10-2.40 (m, 3 H), 1.81-1.97 (m, 1 H), 1.27-1.45(m, 1 H), 0.58-0.70 (m, 2 H), 0.34-0.49 (m, 2 H) 205

P1 L18 3, 7, 9 364 ¹H NMR (400 MHz, dmso-d₆) δ 8.79 (br. s, 1 H), 8.16(s, 1 H), 7.90 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (s, 2 H), 7.44 (d, 1H), 5.31 (t, 1 H), 4.60 (dd, 1 H), 4.27 (dd, 1 H), 3.98-4.10 (m, 1 H),3.97 (s, 3 H), 3.56-3.72 (m, 1 H), 2.69-2.85 (m, 1 H), 2.06-2.21 (m, 1H) 206

P24 17342- 08-4 commer- cial 6, 7 316 ¹H NMR (400 MHz, dmso-d₆) δ 8.91(s, 1 H), 8.41 (s, 1 H), 8.14 (br. s., 2 H), 7.83 (br. s., 1 H), 7.70(br. s., 1 H), 7.53 (s, 1 H), 4.21-4.24 (m, 1 H), 4.11-4.15 (m, 1 H),4.04-4.06 (m 1 H), 4.02 (s, 3 H), 2.20-2.35 (m, 3 H), 1.0-1.93 (m, 1 H)207

P5 L18 5, 9 363 ¹H NMR (400 MHz, dmso-d₆) δ 8.75 (br. s, 1 H), 8.48 (br.s, 1 H), 8.28 (s, 1 H), 7.78 (br. s, 1 H), 7.68 (s, 1 H), 7.62 (br. s.,1 H), 7.54 (d, 1 H), 7.32 (t, 1 H), 7.02 (d, 1 H), 4.23 (dd, 1 H),3.99-4.11 (m, 2 H), 3.97 (s, 3 H), 3.59-3.71 (m, 2 H), 2.72- 2.88 (m, 1H), 2.07-2.28 (m, 1 H) 208

P1 L41 2, 7, 9 378 ¹H NMR (400 MHz, dmso-d₆) δ 8.85 (s, 1 H), 8.15 (s, 1H), 7.79- 7.97 (m, 1 H), 7.61-7.77 (m, 2 H), 7.43 (d, 1 H), 5.25 (br.s., 1 H), 4.57 (dd, 1 H), 4.27 (dd, 1 H), 3.97 (s, 3 H), 3.49-3.80 (m, 2H), 2.80-3.04 (m, 1 H), 1.13 (s, 3 H) 209

P3 17342- 08-4 commer- cial 2, 7 317 ¹H NMR (400 MHz, dmso-d₆) δ 8.71(s, 1 H), 8.22 (br. s, 1 H), 8.03 (s, 1 H), 7.91 (br. s., 1 H), 7.76(br. s., 1 H), 7.62 (s, 1 H), 4.62 (dd, 1 H), 4.31-4.42 (m, 1 H),4.03-4.12 (m, 1 H), 4.00 (s, 3 H), 2.14-2.37 (m, 3 H), 1.85-1.94 (m, 1H) 210

P1 L42 2, 7, 9 378 ¹H NMR (400 MHz, dmso-d₆) δ 9.01 (s, 1 H), 8.16 (s, 1H), 7.90 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (br. s., 1 H), 7.71 (s, 2H), 7.43 (d, 1 H), 5.36 (br. s., 1 H), 4.63 (dd, 1 H), 4.34-4.50 (m, 1H), 4.07-4.24 (m, 1 H), 4.02 (s, 3 H), 3.68 (d, 2 H), 2.77-3.04 (m, 1H), 1.21 (d, 3 H) 211

P1 L36 2, 7 330 ¹H NMR (400 MHz, dmso-d₆) δ 8.15 (s, 1 H), 8.03 (s, 1H), 7.90-7.94 (m, 1 H), 7.85 (s, 1 H), 7.71 (s, 1 H), 7.57 (s, 1 H),7.42-7.44 (m, 1 H), 4.40-4.49 (m, 2 H), 3.97 (s, 3 H), 3.91- 3.94 (m, 1H), 2.66-2.72 (m, 1 H), 2.28-2.34 (m, 1 H), 2.06- 2.12 (m, 1 H),1.07-1.08 (m, 3 H). 212

P2 L43 1, 7, 9 374 ¹H NMR (500 MHz, dmso-d₆) δ 8.14-8.31 (m, 1 H), 8.06(s, 1 H), 7.83-7.98 (m, 1 H), 7.63- 7.82 (m, 3 H), 7.42 (d, 1 H),4.83-5.02 (m, 1 H), 4.50 (dd, 1 H), 4.34 (dd, 1 H), 3.82 (br. s., 1 H),3.47 (br. s., 2 H), 2.32- 2.47 (m, 2 H), 2.03 (dd, 1 H), 1.35-1.46 (m, 6H) 213

P2 L109 1, 7, 9, 21 399 ¹H NMR (400 MHz, dmso-d₆) δ 9.73 (s, 1H),8.18-8.19 (d, 1 H), 8.13 (s, 1 H), 7.87-7.90 (m, 2 H), 7.57-7.59 (d,1H), 7.41- 7.44 (m, 1 H), 4.85-4.90 (m, 1 H), 4.37-4.47 (m, 2 H), 3.80-3.91 (m, 1 H), 3.49-3.52 (m, 1 H), 3.03-3.16 (m, 3 H), 2.73- 2.87 (m, 2H), 2.32-2.49 (m, 3 H), 1.37-1.41 (m, 6 H) 214

P1 L43 1, 7, 9 346 ¹H NMR (500 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.10 (s, 1H), 7.83- 7.98 (m, 2 H), 7.60-7.76 (m, 2 H), 7.43 (d, 1 H), 4.52 (dd, 1H), 4.33 (dd, 1 H), 4.00 (s, 3 H), 3.78-3.87 (m, 1 H), 3.48 (d, 2 H),2.30-2.49 (m, 2 H), 2.02 (dd, 1 H) 215

P1 L23 2, 7 366 ¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1 H), 7.91-7.92 (d, 1H), 7.82 (s, 1 H), 7.37-7.39 (d, 1 H), 4.63-4.86 (m, 3 H), 4.44- 4.48(m, 1 H), 4.22-4.24 (m, 1 H), 4.08 (s, 3 H), 2.89-3.00 (m, 1 H),2.40-2.58 (m, 1 H). 216

P5 L36 5 329 ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1 H), 7.38-7.51 (m, 2H), 7.23 (t, 3 H), 6.82 (d, 1 H), 4.16-4.26 (m, 1 H), 4.04 (dd, 4 H),2.73-2.94 (m, 1 H), 2.51 (dd, 1 H), 2.27 (dd, 1 H), 1.08- 1.16 (m, 3 H)218

P5 L38 5 347 ¹H NMR (500 MHz, dmso-d₆) δ 8.56 (s, 1 H), 8.30 (s, 1 H),7.79 (br. s., 1 H), 7.63 (br. s., 1 H), 7.56 (d, 1 H), 7.43 (s, 1 H),7.33 (t, 1 H), 7.07 (d, 1 H), 5.01-5.23 (m, 1 H), 4.30 (dd, 1 H), 4.01(d, 4 H), 2.68-2.88 (m, 1 H), 1.22 (d, 3 H) 219

P2 L36 1, 7 358 ¹H NMR (500 MHz, dmso-d₆) δ 8.20 (s, 1 H), 7.97 (s, 1H), 7.90 (d, 1 H), 7.73 (d, 2 H), 7.58 (s, 1 H), 7.43 (d, 1 H), 4.87(dt, 1 H), 4.44-4.55 (m, 2 H), 3.80- 3.99 (m, 1 H), 2.66-2.80 (m, 1 H),2.33 (dd, 1 H), 2.09 (dd, 1 H), 1.31-1.47 (m, 6 H), 1.09 (d, 3 H) 220

P25 L37 5 365 ¹H NMR (400 MHz, dmso-d₆) δ 8.57 (s, 1 H), 8.35 (s, 1 H),7.84 (br. s., 1 H), 7.72 (br. s., 1 H), 7.44 (s, 1 H), 7.13 (dd, 1 H),7.01 (dd, 1 H), 5.08 (dd, 1 H), 4.28 (dd, 1 H), 3.99 (s, 3 H), 3.92-4.08(m, 2 H), 2.66-2.83 (m, 1 H), 1.21 (d, 3 H) 221

P1 194421- 58-4 Ref. 31 1, 7, HPLC 344 ¹H NMR (500 MHz, dmso-d₆) δ 8.17(s, 1 H), 8.06 (s, 1 H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (br.s., 1 H), 7.61 (s, 1 H), 7.44 (d, 1 H), 4.47-4.55 (m, 1 H), 4.42 (dd, 1H), 3.61 (t, 1 H), 2.27 (d, 1 H), 2.04 (d, 1 H), 1.22 (s, 3 H), 1.12 (s,3 H) 222

P1 194421- 58-4 Ref. 31 1, 7, HPLC 344 ¹H NMR (500 MHz, dmso-d₆) δ 8.17(s, 1 H), 8.06 (s, 1 H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (br.s., 1 H), 7.61 (s, 1 H), 7.44 (d, 1 H), 4.47-4.55 (m, 1 H), 4.42 (dd, 1H), 3.61 (t, 1 H), 2.27 (d, 1 H), 2.04 (d, 1 H), 1.22 (s, 3 H), 1.12 (s,3 H) 223

P2 194421- 58-4 Ref. 31 1, 7, HPLC 372 ¹H NMR (500 MHz, dmso-d₆) δ 8.19(s, 1 H), 7.99 (s, 1 H), 7.89 (d, 1 H), 7.70 (s, 1 H), 7.73 (s, 1 H),7.60 (s, 1 H), 7.41 (d, 1 H), 4.77-4.94 (m, 1 H), 4.34-4.54 (m, 2 H),3.52-3.64 (m, 1 H), 2.24 (d, 1 H), 2.03 (d, 1 H), 1.38 (d, 3 H), 1.40(d, 3 H), 1.21 (s, 3 H), 1.10 (s, 3 H) 224

P1 L110 7, 2, HPLC 355 ¹H NMR (500 MHz, dmso-d₆) δ 8.50 (s, 1 H), 8.17(s, 1 H), 7.91 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (br. s., 1 H), 7.67(s, 1 H), 7.44 (d, 1 H), 4.63 (dd, 1 H), 4.24 (dd, 1 H), 4.05 (m, 1 H),3.99 (s, 3 H), 2.67-2.84 (m, 3 H), 1.66-1.74 (m, 1 H) 225

P1 L110 7, 2, HPLC 355 ¹H NMR (500 MHz, dmso-d₆) δ 8.46 (s, 1 H), 8.17(s, 1 H), 7.91 (d, 1 H), 7.85 (br. s., 1 H). 7.70 (br. s., 1 H), 7.60(s, 1 H), 7.44 (d, 1 H), 4.49 (dd, 1 H), 4.37 (dd, 1 H), 4.05 (m, 1 H),3.99 (s, 3 H), 2.96 (m, 1 H), 2.73-2.80 (m, 2 H), 2.29 (m, 1 H), 2.12(m, 1 H) 226

P2 L111 2, 7, 10 385 ¹H NMR (400 MHz, dmso-d₆) δ 9.51 (s, 1 H), δ9.24(s, 1 H), δ8.44 (s, 1 H), δ8.20 (s, 1 H), 7.90-7.88 (d, 1 H), 7.72 (s, 2H), δ7.57 (s, 1 H), 7.44-7.43 (d, 1 H), 4.91-4.81 (m, 1 H), 4.48- 4.47(m, 2 H), 3.98-3.92 (m, 1 H), 3.55-3.47 (m, 1 H), 3.37- 3.25 (m, 3 H),3.20-3.16 (m, 1 H), 3.08-3.02 (m, 1 H), 1.41- 1.35 (m, 6 H) 227

P1 127913- 30-8 Ref. 32 2, 7 332 ¹H NMR (400 MHz, dmso-d₆) δ 8.07 (s, 1H), 7.93 (s, 1 H), 7.77-7.81 (m, 2 H), 7.61 (s, 1 H), 7.51 (s, 1 H),7.34-7.35 (d, 1 H), 4.49-4.52 (m, 1 H), 4.38-4.41 (m, 1 H), 4.30-4.34(m, 1 H), 3.87 (s, 3 H), 3.74- 3.75 (m, 1 H), 1.29-1.30 (d, 3 H) 228

P5 127913- 30-8 Ref. 32 6 331 ¹H NMR (400 MHz, dmso-d₆) δ 8.29 (s, 1 H),7.99 (s, 1 H), 7.79 (br. s, 1 H), 7.64 (br. s, 1 H), 7.61 (s, 1 H), 7.54(d, 1 H), 7.32 (t, 1 H), 7.01 (d, 1 H), 4.63 (quin, 1 H), 4.19 (d, 2 H),3.85 (m, 1 H), 1.43 (d, 1 H) 229

P1 15546- 08-4 Ref. 17 2, 7 318 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (m, 1H), 8.08 (m, 1 H), 7.87-7.92 (m, 2 H), 7.73 (m, 1 H), 7.63 (m, 1 H),7.45-7.46 (m, 2 H), 4.49-4.52 (m, 2 H), 4.38-4.417 (m, 1 H), 4.28- 4.32(m, 2 H), 3.98 1 (s, 3 H) 230

P1 15546- 08-4 Ref. 17 6 318 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (m, 1 H),8.08 (m, 1 H), 7.87-7.92 (m, 2 H), 7.73 (m, 1 H), 7.63 (m, 1 H),7.45-7.46 (m, 2 H), 4.49-4.52 (m, 2 H), 4.38-4.417 (m, 1 H), 4.28- 4.32(m, 2 H), 3.98 1 (s, 3 H) 231

P5 L25 6, HPLC 345 ¹H NMR (400 MHz, dmso-d₆) δ 8.44 (s, 1 H), δ8.28 (s,1 H), 7.80 (s, 1 H), 7.67-7.65 (m, 2 H), 7.54-7.52 (m, 1 H), 7.33- 7.29(m, 1 H), 7.01-7.00 (m, 1 H), 4.20-4.19 (m, 1 H), 4.03- 3.94 (m, 6 H),3.44 (s. 3 H), 2.61-2.58 (m, 1 H), 1.85-1.84 (m, 1 H) 232

P5 L25 6, HPLC 345 ¹H NMR (400 MHz, dmso-d₆) δ 8.35 (s, 1 H), δ8.29 (s,1 H), 7.80 (s, 1 H), 7.65 (s, 1 H), 7.55- 7.54 (m, 2 H), 7.34-7.30 (m, 1H), 7.02-7.00 (m, 1 H), 4.19-4.15 (m, 1 H), 4.12-4.10 (m, 2 H), 4.01 (s,3 H), 3.46 (s, 3 H), 2.41-2.33 (m, 1 H), 2.17-2.13 (m, 1 H) 233

P5 15546- 08-4 Ref. 17 6 317 ¹H NMR (400 MHz, dmso-d₆) δ 8.29 (m, 1 H),8.01 (m, 1 H), 7.80 (m, 1 H), 7.62-7.65 (m, 2 H), 7.53-7.55 (m, 1 H),7.00- 7.02 (m, 1 H), 4.50-4.52 (s, 1 H), 4.36-4.37 (s, 1 H), 4.34 (m, 1H), 4.17-4.18 (m, 2 H), 3.98 (s, 3 H) 234

P5 L112 5 331 ¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1 H), 7.72 (s, 1 H),7.49 (d, 1 H), 7.32 (t, 1 H), 7.00 (d, 1 H), 4.97-5.07 (m, 1 H), 4.32(dd, 1 H), 4.23 (dd, 1 H), 4.14- 4.20 (m, 1 H), 4.08 (s, 3 H), 1.51 (d,3 H) 235

P1 97859- 49-9 Ref. 11 3, 7 318 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1H), 7.91 (d, 1 H), 7.84 (bs, 1 H), 7.70 (bs, 1 H), 7.67 (bs, 1 H), 7.53(s, 1 H), 7.46 (d, 1 H), 5.06 (m, 1 H), 4.62 (m, 2 H), 3.96 (s, 3 H),3.70 (m, 1 H), 3.45 (m, 1 H) 236

P1 L112 3, 7 332 ¹H NMR (400 MHz, dmso-d₆) δ 8.16 (s, 1 H), 7.91 (d, 1H), 7.89 (s, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.62 (s, 1H), 7.44 (d, 1 H), 4.87 (quin, 1 H), 4.42- 4.53 (m, 2 H), 4.10-4.18 (m,1 H), 3.97 (s, 3H), 1.37 (d, 3 H) 237

P1 L44 4, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.83 (s, 1 H), 8.17 (s, 1H), 7.85-7.93 (m, 2 H), 7.63- 7.70 (m, 2 H), 7.45-7.46 (m, 1 H),4.55-4.59 (m, 1 H), 4.32- 4.37 (m, 1 H), 4.01-4.16 (m, 1 H), 4.00 (s, 3H), 2.51 (m, 1 H), 1.40-1.46 (m, 3 H), 1.09-1.11 (m, 3 H) 238

P1 L45 4, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.95 (s, 1 H), 8.16 (s, 1H), 7.85-7.92 (m, 2 H), 7.69-7.74 (m, 2 H), 7.43-7.44 (m, 1 H),4.56-4.59 (m, 1 H), 4.24-4.28 (m, 1 H), 4.00-4.06 (m, 1 H), 3.99 (s, 3H), 2.51 (m, 1 H), 1.40-1.46 (m, 3 H), 1.13-1.15 (m, 3 H) 239

P1 1315020- 11-1 commer- cial 2, 7 332 ¹H NMR (400 MHz, dmso-d₆) δ 8.19(m, 1 H), 7.87-7.93 (m, 2 H), 7.73 (s, 1 H), 7.46-7.48 (m, 2 H),5.00-5.02 (m, 1 H), 4.58-4.68 (m, 2 H), 4.00 (s, 3 H), 3.77-3.81 (m, 1H), 3.52- 3.54 (m, 1 H), 2.83 (s, 3 H) 240

P5 L26 6 415 ¹H NMR (400 MHz, CDCl₃) δ 8.62 (s, 1 H), 7.81-7.82 (m, 1H), 7.44-7.50 (m, 2 H), 7.22-7.24 (m, 1 H), 6.78-6.80 (m, 1 H), 6.55 (s,1 H), 5.87 (s, 1 H), 4.03-4.22 (m, 3 H), 4.00 (s, 3 H), 2.70-3.07 (m, 2H), 2.41-2.63 (m, 2 H) 241

P5 L26 6 415 ¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1 H), 7.61 (s, 1 H),7.40- 7.42 (m, 1 H), 7.21-7.25 (m, 1 H), 6.93-6.95 (m, 1 H), 4.09- 4.21(m, 3 H), 3.97 (s, 3 H), 2.23- 3.03 (m, 4 H) 242

P1 L1 2, 7, HPLC 330 ¹H NMR (400 MHz, dmso-d₆) δ 8.17-8.21 (m, 2 H)7.90-7.91 (m, 2 H), 7.68-7.72 (m, 2 H), 7.43-7.44 (m, 1 H), 4.58-4.60(m, 1 H), 4.18-4.22 (m, 1 H), 4.00 (s, 4 H), 2.68 (m, 1 H), 2.34 (m, 1H), 1.47-1.48 (m, 1 H), 1.11-1.13 (d, 3 H) 243

P1 L1 2, 7, HPLC 330 ¹H NMR (400 MHz, CD₃OD) δ 8.23 (m, 2 H), 7.78-7.80(m, 1 H), 7.61 (m, 1 H), 7.25-7.26 (m, 1 H), 4.39-4.47 (m, 2 H),4.04-4.05 (m, 1 H), 3.98 (s, 3 H), 2.63-2.65 (m, 1 H), 2.27 (m, 1 H),1.94-1.98 (m, 1 H), 1.12-1.14 (d, 3 H) 244

P1 L46 2, 7 344 ¹H NMR (400 MHz, dmso-d₆) δ 8.04 (s, 1 H), 8.01 (s, 1H), 7.75- 7.79 (m, 2 H), 7.60 (s, 1 H), 7.52 (s, 1 H), 7.31-7.32 (m, 1H), 4.37-4.48 (m, 1 H), 4.17- 4.22 (m, 1 H), 3.87 (s, 3 H), 3.55-3.58(m, 1 H), 2.52-2.55 (m, 1 H), 1.97-2.03 (m, 1 H), 1.77-1.82 (m, 1 H),1.46-1.50 (m, 1 H), 1.34-1.35 (m, 1 H), 0.79-0.83 (m, 3 H) 245

P1 L27 2, 7 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.22 (s, 1 H), 8.15 (s, 1H), 7.90 (d, 1 H), 7.85 (br. s, 1 H), 7.70 (br. s, 1 H), 7.65 (s, 1 H),7.42 (d, 1 H), 4.52-4.55 (m, 1 H), 4.29-4.33 (m, 1 H), 4.12 (m, 1 H),3.99 (s, 3 H), 2.38-2.41 (m, 1 H), 1.97-2.01 (m, 1 H), 0.86 (m, 2 H),0.75 (m, 2 H) 246

P1 L47 3, 7 344 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.06 (s, 1H), 7.86- 7.92 (m, 2 H), 7.73 (s, 1 H), 7.57 (s, 1 H), 7.43-7.45 (m, 1H), 4.45 (d, 2 H), 3.99 (s, 3 H), 3.96-3.98 (m, 1 H), 2.34- 2.12 (m, 3H), 1.55-1.64 (m, 1 H), 1.35-1.45 (m, 1 H), 0.92- 0.95 (m, 3 H) 247

P1 L48 2, 7, HPLC 344 ¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1 H), 7.79-7.80(m, 1 H), 7.64 (s, 1 H), 7.24-7.25 (m, 1 H), 4.53-4.54 (m, 1 H),4.39-4.41 (m, 1 H), 4.09-4.11 (m, 1 H), 3.99 (s, 3 H), 2.59- 2.78 (m, 2H), 1.05-1.07 (m, 3 H), 0.93-0.95 (m, 3 H) 248

P1 L48 2, 7, HPLC 344 ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1 H), 7.79-7.81(m, 1 H), 7.53 (s, 1 H), 7.25-7.27 (m, 1 H), 4.46-4.53 (m, 2 H), 3.96(s, 3 H), 3.89-3.91 (m, 1 H), 2.29-2.33 (m, 2 H), 1.10- 1.13 (m, 6 H)249

P1 L49 2, 7 348 ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1 H), 7.91 (d, 1 H),7.78 (s, 1 H), 7.48 (d, 1 H), 4.62- 4.66 (m, 3 H), 4.51-4.55 (m, 1 H),4.13-4.15 (m, 1 H), 4.11 (s, 3 H), 2.83-2.96 (m, 1 H), 2.68-2.78 (m, 1H), 2.27-2.32 (m, 1 H). 250

P16 L38 3, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 10.18 (s, 1 H), 8.76 (s, 1H), 8.63 (d, 1 H), 7.81 (br. s., 1 H), 7.60-7.71 (m, 2 H), 7.09 (d, 1H), 4.99 (d, 1 H), 4.86 (d, 1 H), 4.30 (dd, 1 H), 4.02-4.19 (m, 2 H),3.96 (s, 3 H), 2.76-2.99 (m, 1 H), 1.09 (d, 3 H) 251

P1 L50 3, 7 342 ¹H NMR (600 MHz, dmso-d₆) δ 8.16 (s, 1 H) 8.13 (s, 1 H)7.90 (d, 1 H) 7.83 (br. s., 1 H) 7.67- 7.71 (m, 1 H) 7.58 (s, 1 H) 7.42(d, 1 H) 5.94 (ddd, 1 H) 5.20 (d, 1 H) 5.11 (d, 1 H) 4.40-4.46 (m, 1 H)4.30-4.38 (m, 1 H) 4.01-4.09 (m, 1 H) 3.32-3.41 (m, 1 H) 2.37-2.47 (m, 1H) 2.27-2.36 (m, 1 H) 252

P1 L2 2, 7, HPLC 334 ¹H NMR (400 MHz, dmso-d₆) δ 8.90 (s, 1 H), 8.35 (s,1 H), 8.09 (d, 1 H), 8.05 (br, s, 1 H), 7.90 (br. s, 1 H), 7.81 (s, 1H), 7.63 (d, 1 H), 5.25-5.42 (m, 1 H), 4.77 (dd, 1 H), 4.43-4.48 (m, 1H), 4.23 (m, 1 H), 4.16 (s, 3 H), 2.85-3.00 (m, 1 H), 2.19- 2.32 (m, 1H) 253

P1 L2 2, 7, HPLC 334 ¹H NMR (400 MHz, dmso-d₆) δ 9.01 (s, 1 H),8.36-8.38 (m, 1 H), 8.06-8.12 (m, 2 H), 7.92 (br. s, 1 H), 7.77-7.79 (m,1 H), 7.65-7.66 (m, 1 H), 5.42-5.57 (m, 1 H), 4.69-4.71 (m, 1 H)4.50-4.55 (m, 1 H), 4.35 (m, 1 H), 4.18-4.20 (m, 3 H), 2.53- 2.62 (m, 2H) 254

P1 L52 2, 7, HPLC 362 ¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1 H), 7.89 (d,1 H), 7.73 (s, 1 H), 7.36 (d, 1 H), 4.66- 4.73 (m, 2 H), 4.58-4.62 (m, 1H), 4.45-4.49 (m, 1 H), 4.08 (s, 3 H), 4.01-4.07 (m, 1 H), 2.43-2.49 (m,1 H), 2.32-2.40 (m, 1 H), 1.29 (d, 3 H) 255

P1 66673- 40-3 commer- cial 3, 7 316 ¹H NMR (400 MHz, CD₃OD) δ 8.36 (s,1 H), 7.92 (d, 1 H), 7.74 (s, 1 H), 7.38 (d, 1 H), 4.55-4.66 (m, 1 H),4.49 (dd, 1 H), 4.20- 4.31 (m, 1 H), 4.11 (s, 3 H), 2.36-2.63 (m, 3 H),2.05-2.19 (m, 1 H) 256

P1 L8 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.92 (s, 1 H), 8.18 (s, 1 H),7.92 (d, 1 H), 7.87 (br. s., 1 H), 7.73 (br. s., 1 H), 7.66 (s, 1 H),7.46 (d, 1 H), 4.63 (dd, 1 H), 4.22- 4.30 (m, 1 H), 4.12-4.22 (m, 1 H),2.39-2.50 (m, 1 H), 2.09- 2.26 (m, 1 H), 1.95 (ddd, 1 H), 1.62-1.82 (m,1 H), 0.98 (t, 3 H) 257

P1 L7 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.82 (s, 1 H), 8.18 (s, 1 H),7.92 (d, 1 H), 7.86 (br. s., 1 H), 7.72 (s, 2 H), 7.45 (d, 1 H), 4.60(dd, 1 H), 4.27 (dd, 1 H), 3.90-4.09 (m, 4 H), 2.59 (td, 1 H), 2.12-2.27 (m, 1 H), 1.92 (td, 1 H), 1.66-1.81 (m, 1 H), 0.97 (t, 3 H) 258

P1 L28 3, 7 406 ¹H NMR (600 MHz, dmso-d₆) δ 8.11-8.22 (m, 2 H), 7.87 (d,1 H), 7.81 (br. s., 1 H), 7.65 (br. s., 1 H), 7.58 (s, 1 H), 7.41 (d, 1H), 7.16-7.32 (m, 5 H), 4.46 (dd, 1 H), 4.28 (dd, 1 H), 3.93- 4.01 (m, 3H), 3.86-3.93 (m, 1 H), 3.07 (dd, 1 H), 2.83 (dd, 1 H), 2.61 (dd, 1 H),1.99 (dd, 2 H) 259

P16 L7 3, 7 362 ¹H NMR (500 MHz, CD₃OD) δ 8.63 (d, 1 H), 8.50 (s, 1 H),7.80 (s, 1 H), 7.05 (d, 1 H), 4.42 (dd, 1 H), 4.28 (dd, 1 H), 4.19 (dt,1 H), 4.08 (s, 3 H), 2.68-2.82 (m, 1 H), 2.37-2.50 (m, 1 H), 2.00- 2.14(m, 1 H), 1.80-1.96 (m, 1 H), 1.09 (t, 3 H) 260

P16 L8 3, 7 362 ¹H NMR (500 MHz, CD₃OD) δ 8.62 (d, 1 H), 8.48 (s, 1 H),7.68 (s, 1 H), 7.06 (d, 1 H), 4.32- 4.46 (m, 2 H), 4.24 (dd, 1 H), 4.08(s, 3 H), 2.53-2.68 (m, 1 H), 2.21-2.36 (m, 1 H), 2.09 (ddd, 1 H),1.74-1.90 (m, 1 H), 1.07 (t, 3 H) 261

P1 L24 3, 7 366 ¹H NMR (400 MHz, dmso-d₆) δ 9.16 (s, 1 H), 8.19 (s, 1H), 7.92 (d, 1 H), 7.86 (br. s., 1 H), 7.71 (br. s., 1 H), 7.66 (s, 1H), 7.46 (d, 1 H), 4.78-4.90 (m, 1 H), 4.61-4.77 (m, 2 H), 4.20-4.36 (m,2 H), 4.00 (s, 3 H), 2.55-2.67 (m, 1 H), 2.35-2.49 (m, 1 H) 262

P16 17342- 08-4 commer- cial 3, 7 316 ¹H NMR (500 MHz, dmso-d₆) δ 8.64(d, 1 H), 8.20 (s, 1 H), 8.16 (s, 1 H), 7.84 (br. s., 1 H), 7.68 (br.s., 1 H), 7.58 (s, 1 H), 7.04 (d, 1 H), 4.26 (dd, 1 H), 4.15 (dd, 1 H),4.05-4.12 (m, 1 H), 4.00 (s, 3 H), 2.17-2.40 (m, 3 H), 1.89- 1.97 (m, 1H) 263

P1 L73 3, 7 356 ¹H NMR (500 MHz, CD₃OD) δ 8.35 (s, 1 H), 7.91 (d, 1 H),7.76 (s, 1 H), 7.37 (d, 1 H), 4.61 (dd, 1 H), 4.55 (dd, 1 H), 4.11 (s, 3H), 3.94 (s, 1 H), 2.68 (s, 1 H), 1.91 (d, 1 H), 1.86 (dd, 1 H), 1.24(s, 3 H), 1.21 (s, 3 H) 264

P1 L72 3, 7 328 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 1 H), 7.92 (d, 1H), 7.86 (br. s., 1 H), 7.71 (br. s., 1 H), 7.64 (s, 2 H), 7.45 (d, 1H), 4.49 (dd, 1 H), 4.41 (dd, 1 H), 4.01 (s, 3 H), 3.90 (t, 1 H),1.92-2.05 (m, 1 H), 1.78 (br. s., 1 H), 1.10 (td, 1 H), 0.60 (q, 1 H)265

P1 1004-59- Ref. 33 1, 7 346 Rt = 2.037 min; method PF-AB01 266

P1 29-8-2 Ref. 34 1, 7 332 Rt = 2.043 min; method PF-AB01 267

P1 L15 3, 7 398 ¹H NMR (400 MHz, dmso-d₆) δ 8.50 (br. s., 1 H), 8.23 (s,1 H), 7.97 (d, 1 H), 7.90 (br. s., 1 H), 7.76 (br. s., 1 H), 7.63 (s, 1H), 7.50 (d, 1 H), 4.60 (d, 1 H), 4.45 (d, 1 H), 4.08 (br. s., 1 H),4.03 (s, 3 H), 2.93 (d, 1 H), 2.75 (br. s., 1 H), 2.37 (d, 2 H), 2.25(br. s., 1 H) 268

P16 L10 3, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 8.83 (s, 1 H), 8.65 (d, 1H), 8.20 (s, 1 H), 7.85 (br. s., 1 H), 7.69 (br. s., 1 H), 7.67 (s, 1H), 7.05 (d, 1 H), 4.35 (dd, 1 H), 4.03- 4.17 (m, 2 H), 3.99 (s, 3 H),2.54-2.63 (m, 1 H), 2.23-2.38 (m, 1 H), 1.52 (d, 3 H) 269

P15 L10 3, 7 376 ¹H NMR (400 MHz, dmso-d₆) δ 8.78 (s, 1 H), 8.64 (d, 1H), 8.24 (s, 1 H), 7.63-7.79 (m, 3 H), 7.04 (d, 1 H), 4.90 (dt, 1 H),4.34 (dd, 1 H), 3.99-4.20 (m, 3 H), 3.18 (d, 1 H), 2.54-2.62 (m, 1 H),2.23-2.38 (m, 1 H), 1.52 (d, 1 H), 1.39 (d, 3 H), 1.41 (d, 3 H) 270

P1 L16 3, 7 398 ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1 H), 7.93 (d, 1 H),7.80 (br. s., 1 H), 7.56 (s, 1 H), 7.33 (d, 1 H), 6.39 (br. s., 1 H),5.94 (br. s., 1 H), 4.78 (dd, 1 H), 4.39 (dd, 1 H), 4.20 (d, 1 H), 4.11(s, 3 H), 2.76-3.01 (m, 2 H), 2.66-2.76 (m, 1 H), 2.10 (dt, 1 H),1.69-1.82 (m, 1 H) 271

P1 L74 3, 7 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 1 H), 7.92 (d, 1H), 7.86 (br. s., 1 H), 7.71 (s, 1 H), 7.64 (s, 1 H), 7.62 (s, 1 H),7.45 (d, 1 H), 4.47 (dd, 1 H), 4.36 (dd, 1 H), 4.01 (s, 3 H), 3.87-3.94(m, 1 H), 1.73-1.82 (m, 1 H), 1.59 (d, 1 H), 1.10 (d, 3 H), 0.98- 1.06(m, 1 H) 272

P1 L38 3 330 ¹H NMR (600 MHz, dmso-d₆) δ 8.72 (s, 1 H), 8.49 (s, 1 H),7.98 (d, 1 H), 7.78 (s, 1 H), 7.41 (d, 1 H), 4.92 (dd, 1 H), 4.58 (dd, 1H), 4.28 (dd, 1 H), 3.99-4.08 (m, 4 H), 2.79-2.92 (m, 1 H), 1.08 (dd, 3H) 273

P1 3637-61- 4 commer- cial 3, 7 301 ¹H NMR (400 MHz, dmso-d₆) δ 8.16 (s,1 H), 7.89 (d, 1 H), 7.82 (br. s., 1 H), 7.68 (br. s., 1 H), 7.53 (s, 1H), 7.39 (d, 1 H), 4.37 (d, 2 H), 3.97 (s, 3 H), 2.42-2.50 (m, 1 H),1.80-1.85 (m, 2 H), 1.58-1.66 (m, 4 H), 1.40- 1.46 (m, 2 H) 274

P16 L29 3, 7 380 ¹H NMR (600 MHz, dmso-d₆) δ 8.88 (s, 1 H), 8.59-8.65(m, 1 H), 8.17-8.22 (m, 1 H), 7.79 (br. s., 1 H), 7.65 (s, 1 H), 7.61(br. s., 1 H), 7.00-7.05 (m, 1 H), 4.60-4.76 (m, 2 H), 4.30- 4.39 (m, 1H), 4.04-4.20 (m, 3 H), 3.94-4.00 (m, 3 H), 2.61- 2.73 (m, 1 H),2.13-2.36 (m, 3 H) 275

P1 L3 3, 7 334 ¹H NMR (400 MHz, dmso-d₆) δ 8.77 (s, 1 H), 8.18 (s, 1 H),7.92 (d, 1 H), 7.86 (br. s., 1 H), 7.70 (s, 2 H), 7.45 (d, 1 H), 5.16(ddd, 1 H), 4.61 (dd, 1 H), 4.28 (dd, 1 H), 4.04 (br. s., 1 H), 3.98 (s,3 H), 2.65-2.84 (m, 1 H), 1.98- 2.18 (m, 1 H) 276

P1 L29 3, 7 380 ¹H NMR (400 MHz, dmso-d₆) δ 8.95 (s, 1 H), 8.18 (s, 1H), 7.92 (d, 1 H), 7.86 (br. s., 1 H), 7.72 (s, 2 H), 7.45 (d, 1 H),4.70-4.85 (m, 1 H), 4.54-4.70 (m, 2 H), 4.28 (dd, 1 H), 4.02- 4.13 (m, 1H), 3.99 (s, 3 H), 2.58-2.75 (m, 1 H), 2.12-2.41 (m, 3 H) 277

P1 L35 3, 7 330 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 1 H), 8.03 (s, 1H), 7.93 (d, 1 H), 7.85 (br. s., 1 H), 7.71 (br. s., 1 H), 7.60 (s, 1H), 7.45 (d, 1 H), 4.39-4.55 (m, 2 H), 3.99 (s, 3 H), 3.91-3.97 (m, 1H), 2.65-2.78 (m, 1 H), 2.34 (dd, 1 H), 2.11 (dd, 1 H), 1.10 (d, 3 H)278

P7 L10 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.79 (s, 1 H), 8.17 (s, 1H), 7.89 (d, 1 H), 7.78 (br. s., 1 H), 7.69 (s, 2 H), 7.43 (d, 1 H),4.60 (dd, 1 H), 4.21-4.31 (m, 3 H), 3.99- 4.00 (m, 1 H), 2.21-2.33 (m, 2H), 1.43-1.52 (m, 6 H) 279

P17 L38 3, 7 362 ¹H NMR (600 MHz, dmso-d₆) δ 8.96 (d, 1 H) 8.78 (s, 1 H)8.30 (s, 1 H) 7.84 (br. s., 1 H) 7.82 (br. s., 1 H) 7.76 (s, 1 H) 7.48(d, 1 H) 4.92 (dd, 1 H) 4.51 (dd, 1 H) 4.29-4.36 (m, 2 H) 4.23-4.29 (m,1 H) 4.10-4.15 (m, 1 H) 2.85-2.95 (m, 1 H) 1.45 (t, 3 H) 1.10 (dd, 3 H)280

P17 L72 3, 7, HPLC 342 ¹H NMR (600 MHz, dmso-d₆) δ 8.98 (br. s., 1 H),8.47 (d, 1 H), 8.32 (s, 1 H), 8.16 (s, 1 H), 6.79 (d, 1 H), 5.08 (br.s., 2 H), 4.37 (q, 2 H), 4.10 (br. s., 1 H), 3.83 (dd, 1 H), 3.69 (dd, 1H), 1.80-1.88 (m, 1 H), 1.74-1.79 (m, 1 H), 1.48 (t, 3 H), 1.26 (td, 1H), 1.05-1.11 (m, 1 H) 281

P21 L38 3, 7 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.67 (s, 1 H), 8.12 (s, 1H), 8.06 (s, 1 H), 7.93 (d, 1 H), 7.66 (br. s., 2 H), 7.44 (d, 1 H),4.99 (dd, 1 H), 4.50 (dd, 1 H), 4.42 (dd, 1 H), 3.96-4.12 (m, 2 H),2.78- 2.98 (m, 1 H), 1.11 (dd, 3 H), 0.89-1.02 (m, 2 H), 0.80-0.89 (m, 1H), 0.69-0.80 (m, 1 H) 282

P7 L72 3, 7 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 7.91 (d, 1H), 7.80 (br. s., 1 H), 7.73 (br. s., 1 H), 7.63 (s, 2 H), 7.44 (d, 1H), 4.49 (dd, 1 H), 4.39 (dd, 1 H), 4.18- 4.35 (m, 2 H), 3.89 (t, 1 H),1.94-2.05 (m, 1 H), 1.77 (br. s., 1 H), 1.47 (t, 3 H), 1.10 (td, 1 H),0.60 (q, 1 H) 283

P7 L38 3, 7 361 ¹H NMR (400 MHz, dmso-d₆) δ 8.77 (s, 1 H), 8.18 (s, 1H), 7.91 (d, 1 H), 7.79 (br. s., 1 H), 7.72 (s, 2 H), 7.44 (d, 1 H),4.95 (dd, 1 H), 4.58 (dd, 1 H), 4.18-4.37 (m, 3 H), 4.05 (br. s., 1 H),2.78- 2.98 (m, 1 H), 1.46 (t, 3 H), 1.05- 1.16 (m, 3 H) 284

P1 L31 3, 7 417 ¹H NMR (400 MHz, dmso-d₆) δ 8.88 (s, 1 H), 8.16 (s, 1H), 7.90 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (s, 2 H), 7.43 (d, 1 H),4.57 (dd, 1 H), 4.25 (dd, 1 H), 3.87-3.96 (m, 6 H), 2.62-2.68 (m, 1 H),2.07-2.19 (m, 2 H), 1.70 (d, 1 H), 1.33-1.43 (m, 3 H) 285

P1 L75 3, 7 341 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 1 H), 7.92 (d, 1H), 7.86 (br. s., 1 H), 7.83 (s, 1 H), 7.71 (br. s., 1 H), 7.66 (s, 1H), 7.45 (d, 1 H), 4.56 (dd, 1 H), 4.40 (dd, 1 H), 4.01 (s, 3 H), 3.74(br. s., 1 H), 1.83-1.98 (m, 2 H), 1.31-1.42 (m, 1 H), 1.06 (d, 3 H) 286

P1 L30 3, 7 399 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 8.16 (s, 1H), 7.89 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (br. s., 1 H), 7.62 (s, 1H), 7.42 (d, 1 H), 4.47 (dd, 1 H), 4.28 (dd, 1 H), 3.95-3.99 (m, 4 H),3.85 (dd, 2 H) 3.24-3.29 (m, 2 H), 2.02-2.14 (m, 1 H) 1.93- 2.02 (m, 1H), 1.82-1.93 (m, 1 H), 1.72 (d, 1 H), 1.45 (dq, 1 H), 1.20-1.38 (m, 3H)287

P17 L10 3, 7 361 ¹H NMR (400 MHz, dmso-d₆) δ 8.82 (s, 1 H), 8.63 (d, 1H), 8.20 (s, 1 H), 7.78 (br. s., 1 H), 7.70 (br. s., 1 H), 7.64 (s, 1H), 7.03 (d, 1 H), 4.29-4.19 (m, 3 H), 4.11-4.05 (m, 2 H), 2.59-2.50 (m,1 H), 2.29-2.22 (m, 1 H), 1.53-1.43 (m, 6 H) 288

P1 L53 3, 7 347 ¹H NMR (400 MHz, dmso-d₆) δ 8.78 (s, 1 H), 8.17 (s, 1H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.73 (s, 1 H), 7.71 (br. s., 1H), 7.45 (d, 1 H), 4.95 (dd, 1 H), 4.58 (dd, 1 H), 4.30 (dd, 1 H), 4.03-4.11 (m, 1 H), 3.99 (s, 3 H), 2.79-2.98 (m, 1 H), 1.10 (d, 3 H) 289

P1 L20 3, 7 415 ¹H NMR (400 MHz, dmso-d₆) δ 8.26 (s, 1 H), 8.18 (s, 1H), 7.92 (d, 1 H), 7.86 (br. s., 1 H), 7.72 (br. s., 1 H), 7.63 (s, 1H), 7.45 (d, 1 H), 4.66 (s, 1 H), 4.48 (dd, 1 H), 4.32 (dd, 1 H), 4.01(s, 3 H), 3.97 (br. s., 1 H), 3.59-3.69 (m, 4 H), 2.61 (t, 1 H), 2.33(dt, 1 H), 1.93-2.04 (m, 2 H), 1.71-1.78 (m, 1 H), 1.56-1.68 (m, 1 H),1.29 (d, 1 H) 290

P1 L32 3, 7 369 ¹H NMR (400 MHz, dmso-d₆) δ 8.54 (s, 1 H), 8.18 (s, 1H), 7.91 (d, 1 H), 7.86 (br. s., 1 H), 7.71 (s, 1 H), 7.64 (s, 1 H),7.45 (d, 1 H), 5.31-5.46 (m, 2 H), 5.15- 5.27 (m, 2 H), 4.54 (dd, 1 H),4.27 (dd, 1 H), 4.15 (d, 1 H), 4.02 (s, 3 H), 2.77-2.91 (m, 1 H) 291

P17 17342- 08-4 commer- cial 3, 7 329 ¹H NMR (400 MHz, dmso-d₆) δ 8.63(d, 1 H), 8.20 (s, 1 H), 8.15 (s, 1 H), 7.77 (br. s., 1 H), 7.70 (br.s., 1 H), 7.57 (s, 1 H), 7.02 (d, 1 H), 4.28-4.37 (m, 1 H), 4.18-4.28(m, 2 H), 4.10-4.17 (m, 1 H), 4.03-4.10 (m, 1 H), 2.17-2.40 (m, 3 H),1.87-1.97 (m, 1 H), 1.45 (t, 3 H) 292

P1 L33 3, 7 377 ¹H NMR (600 MHz, dmso-d₆) δ 8.80 (s, 1 H), 8.17 (s, 1H), 7.90 (d, 1 H), 7.80 (br. s., 1 H), 7.69 (s, 1 H), 7.63 (br. s., 1H), 7.43 (d, 1 H), 4.59 (dd, 1 H), 4.29 (dd, 1 H), 4.03 (d, 1 H), 3.97(s, 3 H), 3.63 (s, 1 H), 3.61 (d, 1 H), 3.35 (s, 3 H), 2.68-2.77 (m, 1H), 2.14-2.25 (m, 1 H) 293

P17 L23 3, 7 379 ¹H NMR (400 MHz, dmso-d₆) δ 9.04 (s, 1 H), 8.64 (d, 1H), 8.20 (s, 1 H), 7.77 (s, 1 H), 7.70 (s, 1 H), 7.63 (s, 1 H), 7.04 (d,1 H), 4.63-4.82 (m, 2 H), 4.35-4.37 (m, 1 H), 4.14-4.27 (m, 4 H),2.72-2.85 (m, 1 H), 2.20-2.35 (m, 1 H), 1.44 (t, 3 H) 294

P7 L23 3, 7 379 ¹H NMR (400 MHz, dmso-d₆) δ 9.02 (s, 1 H), 8.17 (s, 1H), 7.90 (d, 1 H), 7.78 (br. s., 1 H), 7.71 (br. s., 1 H), 7.68 (s, 1H), 7.44 (d, 1 H), 4.69-4.80 (m, 2 H), 4.59-4.65 (m, 2 H), 4.19-4.31 (m,3 H), 4.10 (br. s., 1 H), 2.70-2.81 (m, 1 H), 2.21-2.28 (m, 1 H), 1.44(t, 3H) 295

P1 L94 3, 7 341 ¹H NMR (400 MHz, dmso-d₆) δ 8.23 (s, 1 H), 7.98 (d, 1H), 7.90 (br. s., 1 H), 7.75 (br. s., 1 H), 7.66 (s, 1 H), 7.47-7.54 (m,2 H), 4.56 (dd, 2 H), 4.05 (s, 3 H), 3.93 (br. s., 1 H), 1.69 (dd, 1 H),1.35 (s, 3 H), 1.05 (dd, 1 H), 0.84 (t, 1 H) 296

P1 L54 3, 8 361 ¹H NMR (400 MHz, dmso-d₆) δ 8.87 (s, 1 H), 8.17 (s, 1H), 7.91 (d, 1 H), 7.85 (br. s., 1 H), 7.75 (s, 1 H), 7.70 (br. s., 1H), 7.44 (d, 1 H), 4.92 (dd, 1 H), 4.55 (dd, 1 H), 4.27 (dd, 1 H), 4.10(br. s., 1 H), 3.98 (s, 3 H), 2.55- 2.73 (m, 1 H), 1.52-1.72 (m, 2 H),1.03 (t, 3 H) 297

P1 L91 3, 7 341 ¹H NMR (600 MHz, dmso-d₆) δ 8.17 (s, 1 H), 7.90 (d, 1H), 7.81 (br. s., 1 H), 7.64 (br. s., 1 H), 7.61 (s, 1 H), 7.55 (s, 1H), 7.42 (d, 1 H), 4.43 (d, 2 H), 3.99 (s, 3 H), 3.79 (t, 1 H), 1.82(dd, 1 H), 1.23 (s, 3 H), 0.94 (dd, 1 H), 0.66 (t, 1 H) 298

P1 L34 3, 7 371 Mixture of rotamers (major/minor): ¹H NMR (400 MHz, 27°C., dmso-d₆) δ 8.30/8.24 (s, 1 H), 8.16/8.17 (s, 1 H), 7.90 (d, 1 H),7.85 (br. s., 1 H), 7.70 (br. s., 1 H), 7.66/7.63 (s, 1 H), 7.43 (d, 1H), 4.30-4.73 (m, 6 H), 4.21 (dd, 1 H), 3.95-4.07 (m, 4 H), 3.09-3.20(m, 1 H), 2.95-3.05 (m, 1 H), 2.82-2.92 (m, 1 H), 2.45 (~1 H), 2.29-3.35(m, <1 H), 2.17-2.25 (m, <1 H), 1.93-2.03 (m, <1 H), 1.02-1.13 (m, 1 H).299

P1 L95 3, 7 355 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 1 H), 7.93 (d, 1H), 7.85 (br. s., 1 H), 7.71 (br. s., 1 H), 7.60 (s, 1 H), 7.49 (s, 1H), 7.45 (d, 1 H), 4.46-4.59 (m, 2 H), 4.00 (s, 3 H), 3.95 (d, 1 H),1.97 (dd, 1 H), 1.70 (d, 1 H), 1.15- 1.28 (m, 1 H), 0.94-1.05 (m, 4 H),0.72 (br. s., 1 H) 300

P1 L76 3, 7 355 ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1 H), 7.93 (d, 1 H),7.82 (br. s., 1 H), 7.60 (s, 1 H), 7.31 (d, 1 H), 5.96 (br. s., 1 H),5.54 (br. s., 1 H), 4.62 (dd, 1 H), 4.50 (dd, 1 H), 4.12 (s, 3 H), 4.09(d, 1 H), 1.69-1.78 (m, 2 H), 1.40 (dd, 2 H), 1.22 (t, 1 H), 1.05 (t, 3H) 301

P1 L77 3, 7 355 ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1 H), 7.94 (d, 1 H),7.80 (br. s., 1 H), 7.62 (s, 1 H), 7.32 (d, 1 H), 6.20 (s, 1 H), 6.12(br. s., 1 H), 4.69 (dd, 1 H), 4.55 (dd, 1 H), 4.12 (s, 3 H), 3.96 (d, 1H), 2.04-2.11 (m, 1 H), 1.95- 2.02 (m, 1 H), 1.49-1.60 (m, 2 H),1.33-1.43 (m, 1 H), 1.13 (t, 3 H) 302

P1 128726- 47-6 commer- cial 3, 7 329 ¹H NMR (400 MHz, dmso-d₆) δ 8.17(s, 1 H), 7.90 (d, 1 H), 7.84 (br. s., 1 H), 7.66-7.75 (m, 2 H), 7.64(s, 1 H), 7.43 (d, 1 H), 4.41 (d, 2 H), 3.99 (s, 3 H), 3.79- 3.89 (m, 1H), 2.19 (t, 2 H), 1.81-2.04 (m, 2 H), 1.61-1.76 (m, 2 H) 303

P1 L78 3, 7 359 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 7.92 (d, 1H), 7.86 (br. s., 1 H), 7.78 (s, 1 H), 7.72 (br. s., 1 H), 7.62 (s, 1H), 7.45 (d, 1 H), 4.38-4.52 (m, 3 H), 4.31 (ddd, 1 H), 4.01 (s, 3 H),3.97 (br. s., 1 H), 2.10 (br. s., 1 H), 1.95 (d, 1 H), 1.49 (d, 1 H) 304

P1 L79 3, 7 359 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 7.92 (d, 1H), 7.85 (br. s., 1 H), 7.77 (s, 1 H), 7.71 (br. s., 1 H), 7.62 (s, 1H), 7.45 (d, 1 H), 4.38-4.53 (m, 3 H), 4.31 (ddd, 1 H), 4.01 (s, 3 H),3.94-3.99 (m, 1 H), 2.08-2.12 (m, 1 H), 1.92-1.97 (m, 1 H), 1.50 (td, 1H) 305

P1 L58 3, 7 355 ¹H NMR (400 MHz, dmso-d₆) δ 8.14 (s, 1 H), 8.04 (s, 1H), 7.89 (d, 1 H), 7.82 (br. s., 1 H), 7.68 (br. s., 1 H), 7.59 (s, 1H), 7.41 (d, 1 H), 4.52-4.64 (m, 2 H), 3.94-3.99 (m, 4 H), 2.19-2.34 (m,2 H), 1.85-1.97 (m, 1 H), 0.70-0.83 (m, 1 H), 0.36-0.50 (m, 2 H),0.09-0.25 (m, 2 H) 306

P1 L80 3, 7 373 ¹H NMR (400 MHz, dmso-d₆) δ 8.10 (s, 1 H), 7.84 (d, 1H), 7.81 (s, 1 H), 7.78 (br. s., 1 H), 7.63 (br. s., 1 H), 7.57 (s, 1H), 7.37 (d, 1 H), 4.52-4.58 (m, 1 H), 4.48 (dd, 1 H), 4.40-4.45 (m, 1H), 4.32 (dd, 1 H), 3.93 (s, 3 H), 3.72 (t, 1 H), 1.87-1.97 (m, 2 H),1.54-1.81 (m, 2 H), 1.27- 1.39 (m, 1 H) 307

P1 L113 3, 7 327 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 7.92 (d, 1H), 7.86 (br. s., 1 H), 7.79 (s, 1 H), 7.71 (s, 2 H), 7.44 (d, 1 H),4.63- 4.72 (m, 1 H), 4.18-4.29 (m, 2 H), 4.02 (s, 3 H), 2.08-2.15 (m, 1H), 1.75-1.82 (m, 1 H), 0.97 (td, 1 H), 0.85-0.90 (m, 1 H) 308

P1 L97 3, 7 341 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 2 H), 7.90 (d, 1H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.55 (s, 1 H), 7.43 (d, 1H), 4.36 (dd, 1 H), 4.29 (dd, 1 H), 3.99 (s, 3 H), 3.78 (t, 1 H),2.94-3.02 (m, 1 H), 2.87-2.94 (m, 1 H), 2.27-2.46 (m, 2 H), 2.00-2.11(m, 1 H), 1.87-1.97 (m, 1 H) 309

P1 L92 3, 7 359 ¹H NMR (400 MHz, dmso-d₆) δ 8.18 (s, 1 H), 8.01 (br. s.,1 H), 7.92 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.61 (s, 1H), 7.45 (d, 1 H), 4.53 (dd, 1 H), 4.40 (dd, 1 H), 3.98 (s, 3 H),3.73-3.82 (m, 1 H), 2.19-2.28 (m, 1 H), 1.27-1.35 (m, 1 H), 1.21-1.26(m, 3 H) 310

P1 L93 3, 7 359 ¹H NMR (600 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.15 (br. s.,1 H), 7.91 (d, 1 H), 7.80 (br. s., 1 H), 7.64 (br. s., 1 H), 7.61 (s, 1H), 7.43 (d, 1 H), 4.62 (dd, 1 H), 4.42 (dd, 1 H), 3.95 (s, 3 H), 3.64(dd, 1 H), 2.53-2.59 (m, 1 H), 1.98-2.09 (m, 1 H), 1.01 (dd, 3 H) 311

P1 L114 3, 7 396 ¹H NMR (400 MHz, dmso-d₆) δ 8.49 (s, 1 H), 8.19 (s, 1H), 7.93 (d, 1 H), 7.85 (br. s., 1 H), 7.68- 7.74 (br. s., 1 H), 7.62(s, 1 H), 7.47 (d, 1 H), 4.65 (dd, 1 H), 4.49 (dd, 1 H), 4.02-4.08 (m, 1H), 4.01 (s, 3 H), 3.01-3.11 (m, 2 H) 312

P1 L59 3, 7 358 ¹H NMR (400 MHz, dmso-d₆) δ 8.16 (s, 1 H), 8.03 (br. s.,1 H), 7.91 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.59 (s, 1H), 7.43 (d, 1 H), 4.44 (d, 2 H), 3.93-3.98 (m, 4 H), 2.56-2.65 (m, 1H), 2.27 (dd, 1 H), 2.15 (dd, 1 H), 1.48-1.58 (m , 1 H), 1.27-1.44 (m, 3H), 0.88 (t, 3 H) 313

P1 L81 3, 7 372 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 7.90 (d, 1H), 7.84 (br. s., 1 H), 7.64-7.73 (m, 2 H), 7.61 (s, 1 H), 7.43 (d, 1H), 4.46 (dd, 1 H), 4.38 (dd, 1 H), 3.99 (s, 3 H), 3.89-3.95 (m, 1 H),3.25 (s, 3 H), 1.90-1.96 (m, 1 H), 1.85 (s, 1 H), 1.73-1.78 (m, 1 H),1.21-1.31 (m, 2 H) 314

P1 L82 3, 7 372 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 7.91 (d, 2H), 7.85 (br. s., 1 H), 7.71 (br. s., 1 H), 7.63 (s, 1 H), 7.44 (d, 1H), 4.53 (dd, 1 H), 4.37 (dd, 1 H), 3.99 (s, 3 H), 3.77-3.85 (m, 1 H),3.44 (d, 2 H), 3.27 (s, 3 H), 2.05- 2.11 (m, 1 H), 1.97-2.04 (m, 1 H),1.58 (quin, 1 H) 315

P1 L83 3, 7 346 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H), 7.94 (br. s.,1 H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.71 (br. s., 1 H), 7.63 (s, 1H), 7.46 (d, 1 H), 4.81 (d, 1 H), 4.38- 4.51 (m, 2 H), 3.99-4.06 (m, 4H), 2.34-2.50 (m, 2 H) 316

P16 L54 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.87 (s, 1 H), 8.62 (d, 1H), 8.18 (s, 1 H), 7.83 (br. s., 1 H), 7.69 (s, 1 H), 7.67 (br. s., 1H), 7.08 (d, 1 H), 4.92 (dd, 1 H), 4.22- 4.32 (m, 1 H), 4.06-4.16 (m, 2H), 3.96 (s, 3 H), 2.55-2.74 (m, 1 H), 1.52-1.69 (m, 2 H), 1.01 (t, 3 H)317

P1 L96 3, 7 346 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.00 (br. s.,1 H), 7.91 (d, 1 H), 7.83 (br. s., 1 H), 7.68 (br. s., 1 H), 7.59 (s, 1H), 7.44 (d, 1 H), 4.54 (dd, 1 H), 4.42 (dd, 1 H), 3.95 (s, 3 H),3.66-3.77 (m, 1 H), 2.56-2.70 (m, 1 H), 1.68-1.86 (m, 1 H), 0.98-1.12(m, 1 H) 318

P8 17342- 08-4 commer- cial 3, 7 340 ¹H NMR (400 MHz, dmso-d₆) δ 8.14(s, 1 H), 8.06 (br. s, 1 H), 7.92 (d, 1 H), 7.83 (br. s., 1 H), 7.76 (s,1 H), 7.73 (br. s., 1 H), 7.44 (d, 1 H), 5.05 (s, 2 H), 4.50 (dd, 1 H),4.28 (dd, 1 H), 3.96- 4.07 (m, 1 H), 3.67 (s, 1 H), 2.34 (s, 1 H),2.10-2.29 (m, 2 H), 1.90-1.99 (m, 1 H) 319

P8 17342- 08-4 commer- cial 3, 7 340 ¹H NMR (400 MHz, dmso-d₆) δ 8.15(s, 1 H), 8.06 (s, 1 H), 7.95 (d, 1 H), 7.88 (s, 1 H), 7.84 (br. s., 1H), 7.70 (br. s., 1 H), 7.45 (d, 1 H), 7.39 (t, 1 H), 5.68 (dd, 2 H),4.49 (dd, 1 H), 4.29 (dd, 1 H), 4.00-4.07 (m, 1 H), 2.15-2.34 (m, 3 H),1.88-1.94 (m, 1 H) 320

P1 L84 3, 7 378 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 7.91 (d, 1H), 7.88 (s, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.59 (s, 1H), 7.44 (d, 1 H), 5.90 (td, 1 H), 4.47- 4.58 (m, 1 H), 4.38-4.48 (m, 1H), 4.02-4.10 (m, 1 H), 3.99 (s, 3 H), 2.25-2.33 (m, 1 H), 2.09- 2.17(m, 1 H), 1.62-1.74 (m, 1 H) 321

P22 L74 4, 7 376 ¹H NMR (600 MHz, dmso-d₆) δ 8.84 (s, 1 H), 8.22 (s, 1H), 7.86 (br. s., 1 H), 7.69 (br. s., 1 H), 7.58 (s, 1 H), 5.10 (br. s.,1 H), 4.05-4.13 (m, 1 H), 3.97-4.05 (m, 1 H), 3.93 (s, 3 H), 3.39- 3.53(m, 2 H), 1.94 (d, 1 H), 1.47-1.59 (m, 1 H), 1.18 (d, 3 H) 322

P1 L98 3, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.61 (br. s, 1 H), 8.15 (s,1 H), 7.89 (d, 1 H), 7.81 (br. s., 1 H), 7.67 (br. s, 2 H), 7.42 (d, 1H), 4.46 (dd, 1 H), 4.29 (dd, 1 H), 3.91 (s, 3 H), 3.71-3.87 (m, 1 H),3.14-3.27 (m, 1 H), 2.36-2.50 (m, 1 H), 2.19-2.36 (m, 2 H), 1.29-1.49(m, 1 H) 323

P16 L92 3, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.64 (d, 1 H), 8.19 (s, 1H), 7.99 (br. s., 1 H), 7.82 (br. s., 1 H), 7.66 (br. s., 1 H), 7.53 (s,1 H), 7.03 (d, 1 H), 4.27 (d, 2 H), 3.96 (s, 3 H), 3.79 (d, 1 H), 2.22(m, 1 H), 1.27-1.36 (m, 1 H), 1.23 (s, 3 H) 324

P16 L83 3, 7 346 ¹H NMR (400 MHz, dmso-d₆) δ 8.64 (d, 1 H), 8.20 (s, 1H), 7.92 (br. s., 1 H), 7.83 (br. s., 1 H), 7.67 (br. s., 1 H), 7.54 (s,1 H), 7.03 (d, 1 H), 4.82 (d, 1 H), 4.25 (d, 2 H), 4.05 (t, 1 H), 4.00(s, 3 H), 2.37-2.48 (m, 2 H) 325

P16 L96 3, 7 346 1H NMR (400 MHz, dmso-d₆) δ 8.65 (d, 1 H), 8.19 (s, 1H), 8.01 (br. s., 1 H), 7.82 (br. s., 1 H), 7.66 (br. s., 1 H), 7.53 (s,1 H), 7.04 (d, 1 H), 4.30 (d, 2 H), 3.95 (s, 3 H), 3.76 (d, 1 H), 2.56-2.65 (m, 1 H), 1.80 (ddd, 1 H), 1.09 (dt, 1 H) 326

P16 L72 3, 7 328 ¹H NMR (400 MHz, dmso-d₆) δ 8.64 (d, 1 H), 8.19 (s, 1H), 7.83 (br. s., 1 H), 7.67 (br. s., 1 H), 7.61 (s, 1 H), 7.57 (s, 1H), 7.05 (d, 1 H), 4.25-4.33 (m, 1 H), 4.16-4.24 (m, 1 H), 4.00 (s, 3H), 3.88-3.95 (m, 1 H), 1.91-2.04 (m, 1 H), 1.72-1.86 (m, 1 H), 1.11(td, 1 H), 0.62 (q, 1 H) 327

P1 L85 3, 7, 9 358 ¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1 H), 7.89 (d, 1H), 7.72 (s, 1 H), 7.35 (d, 1 H), 4.47- 4.63 (m, 2 H), 4.10 (s, 3 H),4.04-4.08 (m, 1 H), 3.54 (d, 1 H), 3.44-3.50 (m, 1 H), 3.12 (d, 1 H),2.04-2.10 (m, 1 H), 1.93 (br. s., 1 H), 1.33-1.41 (m, 1 H) 328

P1 L86 3, 7, 9 358 ¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1 H), 7.90 (d, 1H), 7.74 (s, 1 H), 7.36 (d, 1 H), 4.52- 4.66 (m, 2 H), 4.09 (s, 3 H),3.99- 4.08 (m, 1 H), 3.82 (dd, 1 H), 3.61 (dd, 1 H), 2.20-2.30 (m, 1 H),2.18 (d, 1 H), 1.66-1.78 (m, 1 H) 329

P1 L51 3, 7 342 1H NMR (400 MHz, dmso-d₆) δ 8.21 (s, 1 H), 8.16 (s, 1H), 7.90 (d, 1 H), 7.84 (br. s., 1 H), 7.69 (br. s., 1 H), 7.64 (s, 1H), 7.43 (d, 1 H), 5.98 (ddd, 1 H), 5.19 (d, 1 H), 5.08 (d, 1 H), 4.55(dd, 1 H), 4.35 (dd, 1 H), 3.99 (s, 3 H), 3.80 (td, 1 H), 2.93 (dt, 1H), 2.47 (d, 1 H), 2.18 (dd, 1 H) 330

P1 L125 3, 7 342 ¹H NMR (400 MHz, dmso-d₆) δ 8.24 (br. s., 1 H), 8.17(s, 1 H), 7.90 (d, 1 H), 7.83 (br. s., 1 H), 7.69 (br. s., 1 H), 7.59(s, 1 H), 7.42 (d, 1 H), 4.33-4.43 (m, 2 H), 3.98 (s, 3 H), 3.58 (t, 1H), 2.65 (d, 1 H), 2.03 (d, 1 H), 0.79-0.90 (m, 1 H), 0.70-0.79 (m, 1H), 0.54-0.70 (m, 2 H) 333

P16 L79 3, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.64 (d, 1 H), 8.20 (s. 1H), 7.84 (br. s., 1 H), 7.76 (s, 1 H), 7.68 (br. S., 1 H), 7.54 (s, 1H), 7.03 (d, 1 H), 4.29 - 4.52 (m, 2 H), 4.22 - 4.29 (m, 2 H), 4.00 (s,3 H), 3.95-3.99 (m, 1 H), 2.05- 2.11 (m, 1 H), 1.94-2.03 (m, 1 H),1.47-1.56 (m, 1 H) 334

P1 L87 3, 7 346 ¹H NMR (600 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.04 (s, 1H), 7.90 (d, 1 H), 7.80 (br. s., 1 H), 7.63 (br. s., 2 H), 7.42 (d, 1H), 5.15 (ddd, 1 H), 4.59 (dd, 1 H), 4.47 (dd, 1 H), 4.00-4.03 (m, 1 H),3.96-4.00 (m, 3 H), 2.49 (dt, 2 H), 2.19-2.26 (m, 2 H) 335

P1 L88 3, 7 360 ¹H NMR (600 MHz, dmso-d₆) δ 8.17 (s, 1 H), 7.96 (d, 1H), 7.90 (d, 1 H), 7.80 (br. s., 1 H), 7.60-7.66 (m, 2 H), 7.43 (d, 1H), 4.54 (dd, 1 H), 4.41 (dd, 1 H), 3.99 (s, 3 H), 3.91 (t, 1 H), 2.39(dd, 1 H), 2.33 (dd, 1 H), 1.61 (d, 3 H) 336

P1 L89 3, 7 360 ¹H NMR (600 MHz, dmso-d₆) δ 8.21 (s, 1 H), 8.14 (s, 1H), 7.88 (d, 1 H), 7.83 (br. s., 1 H), 7.61 (br. s., 1 H), 7.59 (s, 1H), 7.41 (d, 1 H), 4.70 (s, 1 H), 4.64 (dd, 1 H), 4.51 (dd, 1 H), 4.44(dd, 1 H), 3.99-4.02 (m, 1 H), 3.96 (s, 3 H), 3.22-3.31 (m, 1 H), 2.62(dd, 1 H), 2.30 (dd, 1 H) 337

P1 L55 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.65 (br. s, 1 H), 8.17 (s,1 H), 7.91 (d, 1 H), 7.84 (br. s., 1 H), 7.71 (br. s., 1 H), 7.48 (s, 1H), 7.45 (d, 1 H), 5.13 (dd, 1 H), 4.38-4.47 (m, 2 H), 4.01-4.09 (m, 1H), 3.97 (s, 3 H), 2.52- 2.64 (m, 1 H), 1.49-1.69 (m, 2 H), 1.01 (t, 3H)338

P9 L54 3, 7 365 ¹H NMR (400 MHz, dmso-d₆) δ 8.15 (s, 1 H), 7.89 (d, 1H), 7.83 (br. s, 1 H), 7.73 (s, 1 H), 7.68 (br. s, 1 H), 7.42 (d, 1 H),4.89 (dd, 1 H), 4.55 (dd, 1 H), 4.23- 4.26 (m, 1 H), 4.06-4.09 (m, 1 H),1.57-1.63 (m, 2 H), 1.02 (t, 3 H) 339

P10 L54 3, 7 406 ¹H NMR (400 MHz, dmso-d₆) δ 8.87 (br. s, 1 H), 8.27 (s,1 H), 7.91 (d, 1 H), 7.83 (br. s., 1 H), 7.77 (s, 2 H), 7.45 (d, 1 H),4.90 (dd, 1 H), 4.55 (dd, 1 H), 4.35- 4.43 (m, 1 H), 4.30 (s, 1 H), 4.23(dd, 1 H), 4.04-4.14 (m, 1 H), 3.80 (t, 2 H), 3.36 (s, 3 H), 2.61-2.69(m, 1 H), 1.53-1.66 (m, 2 H), 1.02 (t, 3 H) 340

P1 L60 3, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.11 (s, 1H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.71 (br. s., 1 H), 7.58 (s, 1H), 7.44 (d, 1 H), 4.39-4.54 (m, 2 H), 4.00-4.08 (m, 1 H), 3.98 (s, 3H), 3.41-3.56 (m, 2 H), 3.24 (s, 3 H), 2.84-2.98 (m, 1 H), 2.23 (m, 2 H)341

P3 L54 3, 7 363 ¹H NMR (400 MHz, dmso-d₆) δ 8.90 (s, 1 H), 8.71 (s, 1H), 8.03 (s, 1 H), 7.89 (br. s., 1 H), 7.74 (br. s., 1 H), 7.68 (s, 1H), 4.90 (dd, 1 H), 4.66 (dd, 1 H), 4.32 (dd, 1 H), 4.04-4.19 (m, 1 H),3.97 (s, 3 H), 2.53-2.72 (m, 1 H), 1.50-1.68 (m, 2 H), 1.02 (t, 3 H) 342

P1 L66 3, 7 374 ¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1 H), 7.88 (d, 1 H),7.82 (s, 1 H), 7.34 (d, 1 H), 4.68 (dd, 1 H), 4.35-4.48 (m, 1 H), 4.12-4.19 (m, 1 H), 4.10 (s, 3 H), 3.66 (d, 1 H), 3.57 (s, 3 H), 2.45-2.59(m, 1 H), 1.70-1.82 (m, 1 H), 1.53-1.70 (m, 1 H), 1.06 (t, 3 H) 343

P1 L67 3, 7 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.23 (s, 1 H), 8.18 (s, 1H), 7.91 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.51 (s, 1H), 7.45 (d, 1 H), 4.32-4.52 (m, 2 H), 3.99 (s, 3 H), 3.95 (br. s., 1H), 3.86 (d, 1 H), 3.55 (s, 3 H), 2.22-2.37 (m, 1 H), 1.47-1.65 (m, 2H), 0.98 (t, 3 H) 344

P1 L56 3, 7 367 ¹H NMR (400 MHz, dmso-d₆) δ 8.85 (s, 1 H), 8.15 (s, 1H), 7.90 (d, 1 H), 7.83 (br. s., 1 H), 7.73 (s, 1 H), 7.69 (br. s., 1H), 7.43 (d, 1 H), 4.90 (dd, 1 H), 4.54 (dd, 1 H), 4.25 (dd, 1 H), 4.04-4.13 (m, 1 H), 3.97 (s, 3 H), 2.59 (ddd, 1 H) 345

P1 L40 3, 7 380 ¹H NMR (400 MHz, dmso-d₆) δ 9.33 (br. s., 1 H), 8.16 (s,1 H), 7.91 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.60 (s, 1H), 7.45 (d, 1 H), 4.53 (d, 1 H), 4.33 (d, 1 H), 4.09-4.26 (m, 1 H),3.94 (s, 3 H), 2.74-2.98 (m, 1 H), 1.53-1.79 (m, 2 H), 1.04 (t, 3 H) 346

P1 L57 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.78 (br. s, 1 H), 8.17 (s,1 H), 7.90 (d, 1 H), 7.84 (br. s., 1 H), 7.69 (br. s., 1 H), 7.63 (s, 1H), 7.44 (d, 1 H), 5.17 (dd, 1 H), 4.57 (dd, 1 H), 4.34 (dd, 1 H), 3.99(s, 3 H), 3.75-3.84 (m, 1 H), 1.59-1.71 (m, 2 H), 1.46-1.59 (m, 1 H),1.00 (t, 3 H) 347

P1 L63 3, 7 396 ¹H NMR (400 MHz, dmso-d₆) δ 9.33 (br. s., 1 H), 8.17 (s,1 H), 7.92 (d, 1 H), 7.83 (br. s., 1 H), 7.70 (br. s., 1 H), 7.59 (s, 1H), 7.46 (d, 1 H), 4.51-4.59 (m, 1 H), 4.31-4.40 (m, 1 H), 4.19-4.29 (m,1 H), 3.94 (s, 3 H), 3.71-3.80 (m, 1 H), 3.59-3.71 (m, 1 H), 3.28 (s, 3H), 3.17-3.26 (m, 1 H) 348

P1 L61 3, 7 378 ¹H NMR (400 MHz, dmso-d₆) δ 8.86 (s, 1 H), 8.16 (s, 1H), 7.91 (d, 1 H), 7.84 (br. s., 1 H), 7.72 (s, 1 H), 7.70 (br. s., 1H), 7.44 (d, 1 H), 4.95 (dd, 1 H), 4.55 (dd, 1 H), 4.25-4.35 (m, 1 H),4.07-4.18 (m, 1 H), 3.96 (s, 3 H), 3.62-3.73 (m, 1 H), 3.51-3.62 (m, 1H), 3.27 (s, 3 H), 3.00- 3.14 (m, 1 H) 349

P1 L64 3, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.47 (s, 1 H), 8.16 (s, 1H), 7.90 (d, 1 H), 7.85 (br. s., 1 H), 7.70 (s, 2 H), 7.43 (d, 1 H),4.56 (dd, 1 H), 4.21-4.32 (m, 1 H), 4.00 (s, 3 H), 3.88-3.98 (m, 1 H),3.70 (d, 1 H), 3.45 (s, 3 H), 2.69-2.81 (m, 1 H), 0.98 (d, 3 H) 350

P1 L65 3, 7 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.23 (s, 1 H), 8.17 (s, 1H), 7.92 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.52 (s, 1H), 7.45 (d, 1 H), 4.39-4.50 (m, 2 H), 3.99 (s, 3 H), 3.85-3.91 (m, 1H), 3.83 (d, 1 H), 3.55 (s, 3 H), 2.55-2.64 (m, 1 H), 1.15 (d, 3 H) 351

P1 L61 3, 7 378 ¹H NMR (400 MHz, dmso-d₆) δ 8.74 (s, 1 H), 8.18 (s, 1H), 7.92 (d, 1 H), 7.84 (br. s., 1 H), 7.71 (br. s., 1 H), 7.51 (s, 1H), 7.46 (d, 1 H), 5.19 (dd, 1 H), 4.39- 4.50 (m, 2 H), 4.05-4.15 (m, 1H), 3.98 (s, 3 H), 3.57-3.67 (m, 2 H), 3.27 (s, 3 H), 2.86-3.07 (m, 1 H)352

P1 L68 3, 7, 9, 9 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.47 (s, 1 H), 8.14(s, 1 H), 7.89 (d, 1 H), 7.84 (br. s., 1 H), 7.80 (s, 1 H), 7.68 (br.s., 1 H), 7.41 (d, 1 H), 5.71 (d, 1 H), 4.55 (dd, 1 H), 4.23-4.36 (m, 1H), 4.00 (s, 3 H), 3.91-3.99 (m, 1 H), 3.87 (t, 1 H), 1.56-1.69 (m, 1H), 1.40-1.55 (m, 1 H), 0.97 (t, 3 H) 353

P1 L68 3, 7, 9, 9 360 ¹H NMR (400 MHz, dmso-d₆) δ 8.16 (br. s., 2 H),7.91 (d, 1 H), 7.84 (br. s., 1 H), 7.70 (br. s., 1 H), 7.52 (s, 1 H),7.43 (d, 1 H), 5.48 (d, 1 H), 4.34-4.51 (m, 2 H), 4.00-4.09 (m, 1 H),3.97 (s, 3 H), 3.86-3.94 (m, 1 H), 2.09- 2.23 (m, 1 H), 1.56-1.68 (m, 1H), 1.43-1.56 (m, 1 H), 1.01 (t, 3 H) 354

P1 L115 3, 7 330 ¹H NMR (400 MHz, dmso-d₆) δ 8.16 (s, 1 H), 8.14 (s, 1H), 7.89 (d, 1 H), 7.83 (br. s., 1 H), 7.70 (br. s., 1 H), 7.54 (s, 1H), 7.40 (d, 1 H), 5.27 (quin, 1 H), 3.96 (s, 3 H), 3.79-3.88 (m, 1 H),2.09-2.27 (m, 3 H), 1.76-1.88 (m, 1 H), 1.35 (d, 3 H) 355

P1 L116 3, 7 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 1 H), 8.02 (s, 1H), 7.91 (d, 1 H), 7.83 (br. s., 1 H), 7.69 (br. s., 1 H), 7.55 (s, 1H), 7.44 (d, 1 H), 4.53-4.65 (m, 1 H), 4.42- 4.53 (m, 3 H), 3.97-4.04(m, 1 H), 3.97 (s, 3 H), 2.68-2.81 (m, 1 H), 2.20-2.36 (m, 2 H),1.95-2.12 (m, 1 H), 1.66-1.84 (m, 1 H) 356

P1 L70 3, 7, 10 359 ¹H NMR (400 MHz, dmso-d₆) δ 8.99 (br. s, 1 H), 8.48(br. s., 3 H), 8.18 (s, 1 H), 7.93 (d, 1 H), 7.85 (br. s., 1 H), 7.72(br. s., 1 H), 7.69 (s, 1 H), 7.46 (d, 1 H), 4.68-4.76 (m, 1 H),4.42-4.51 (m, 1 H), 4.16-4.24 (m, 1 H), 4.00 (s, 3 H), 2.71-2.80 (m, 1H), 1.47-1.58 (m, 2 H), 1.01 (t, 3 H) 357

P1 L71 3, 7, 10 359 ¹H NMR (400 MHz, dmso-d₆) δ 8.93 (s, 1 H), 8.45 (br.s., 2 H), 8.19 (s, 1 H), 7.92 (d, 1 H), 7.85 (br. s., 1 H), 7.73 (br.s., 1 H), 7.49 (s, 1 H), 7.47 (d, 1 H), 4.46- 4.58 (m, 2 H), 4.11-4.22(m, 1 H), 3.99 (s, 3 H), 3.86-3.95 (m, 1 H), 2.38-2.47 (m, 1 H),1.80-1.95 (m, 1 H), 1.40-1.54 (m, 1 H), 1.02 (t, 3 H) 358

P2 L54 3, 7 390 ¹H NMR (400 MHz, dmso-d₆) δ 8.79 (s, 1 H), 8.17 (s, 1H), 7.88 (d, 1 H), 7.74 (s, 1 H), 7.72 (br. s., 1 H), 7.70 (br. s., 1H), 7.41 (d, 1 H), 4.88 (dt, 1 H), 4.90 (dd, 1 H), 4.52 (dd, 1 H), 4.27(dd, 1 H), 4.01-4.11 (m, 1 H), 2.53- 2.69 (m, 1 H), 1.51-1.68 (m, 2 H),1.38 (t, 6 H), 1.01 (t, 3 H) 359

P7 L54 3, 7 376 ¹H NMR (400 MHz, dmso-d₆) δ 8.85 (s, 1 H), 8.16 (s, 1H), 7.89 (d, 1 H), 7.77 (br. s., 1 H), 7.72 (s, 1 H), 7.70 (br. s., 1H), 7.42 (d, 1 H), 4.90 (dd, 1 H), 4.54 (dd, 1 H), 4.15-4.33 (m, 3 H),4.02-4.13 (m, 1 H), 2.54-2.71 (m, 1 H), 1.52-1.68 (m, 2 H), 1.44 (t, 3H), 1.02 (t, 3 H) 360

P1 L54 3, 7, 12, HPLC 380 ¹H NMR (400 MHz, dmso-d₆) δ 8.86 (s, 1 H),8.20 (s, 1 H), 7.92 (br. s., 1 H), 7.90 (d, 1 H), 7.80 (br. s., 1 H),7.78 (d, 1 H), 4.92 (dd, 1 H), 4.54 (dd, 1 H), 4.25 (dd, 1 H), 4.15 (dd,1 H), 4.01 (s, 3 H), 2.54-2.72 (m, 1 H), 1.54-1.69 (m, 2 H), 1.03 (t, 3H) 361

P1 L54 3, 7, 12, HPLC 380 ¹H NMR (400 MHz, dmso-d₆) δ 8.65 (s, 1 H),7.98 (d, 1 H), 7.93 (br. s., 1 H), 7.89 (s, 1 H), 7.76 (br. s., 1 H),7.47 (dd, 1 H), 4.85 (dd, 1 H), 4.53 (dd, 1 H), 4.42 (dd, 1 H),4.03-4.12 (m, 1 H), 3.97 (s, 3 H), 2.54-2.68 (m, 1 H), 1.53-1.68 (m, 2H), 1.00 (t, 3 H) 362

P1 L47 3, 7, 12, HPLC 362 ¹H NMR (400 MHz, dmso-d₆) δ 8.19 (s, 1 H),8.05 (br. s, 1 H), 7.90 (m, 2 H), 7.80 (br. s, 1 H), 7.60 (s, 1 H),4.38-4.45 (m, 2 H), 4.00 (s, 3 H), 3.94-3.96 (m, 1 H), 2.43-2.45 (m, 1H), 2.24-2.33 (m 1 H), 2.09-2.16 (m 1 H), 1.55-1.60 (m, 1 H), 1.33-1.41(m, 1 H), 0.93 (t, 3 H). 363

P1 L47 3, 7, 12, HPLC 362 ¹H NMR (400 MHz, dmso-d₆) δ 7.98 (d, 1 H),7.94 (br. s, 1 H), 7.89 (s, 1 H), 7.77 (br. s, 1 H), 7.70 (s, 1 H), 7.46(d, 1 H), 4.51-4.55 (dd, 1 H), 4.41-4.45 (dd, 1 H), 3.94 (s, 3 H),3.89-3.92 (m, 1 H), 2.43-2.45 (m 1 H), 2.17- 2.21 (m 2 H), 1.59-1.64 (m1 H), 1.38-1.44 (m, 1 H), 0.91 (t, 3 H). 364

P1 L74 3, 7, 12, HPLC 360 ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1 H), 7.76(d, 1 H), 7.71 (d, 1 H), 4.43-4.58 (m, 2 H), 4.11 (s, 3 H), 4.04 (t, 1H), 1.87 (dd, 1 H), 1.71 (d, 1 H), 1.17 (d, 3 H), 1.07-1.15 (m, 1 H) 365

P1 L74 3, 7, 12, HPLC 360 ¹H NMR (400 MHz, CD₃OD) δ 8.02 (s, 1 H), 7.95(d, 1 H), 7.36 (dd, 1 H), 4.45-4.57 (m, 2 H), 4.09 (s, 3 H), 4.02 (t, 1H), 1.91 (dd, 1 H), 1.68-1.76 (m, 1 H), 1.18 (d, 3 H), 1.08-1.16 (m, 1H) 366

P1 L117 3, 7 348 ¹H NMR (400 MHz, dmso-d₆) δ 8.17 (s, 2 H), 7.91 (d, 1H), 7.83 (br. s., 1 H), 7.69 (br. s., 1 H), 7.60 (s, 1 H), 7.44 (d, 1H), 4.70 (d, 1 H), 4.50-4.61 (m, 2 H), 4.41-4.49 (m, 1 H), 4.04-4.15 (m,1 H), 3.98 (s, 3 H), 2.97-3.13 (m, 1 H), 2.20-2.36 (m, 2 H) 367

P1 L118 3, 7 366 ¹H NMR (400 MHz, dmso-d₆) δ 8.85 (s, 1 H), 8.16 (s, 1H), 7.91 (d, 1 H), 7.83 (br. s., 1 H), 7.70 (s, 1 H), 7.68 (br. s., 1H), 7.45 (d, 1 H), 5.09 (dd, 1 H), 4.81- 4.93 (m, 1 H), 4.68-4.81 (m, 1H), 4.59 (dd, 1 H), 4.36 (dd, 1 H), 4.16-4.25 (m, 1 H), 3.96 (s, 3 H),3.16-3.28 (m, 1 H) 368

P1 L119 3, 7 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.81 (s, 1 H), 8.16 (s, 1H), 7.91 (d, 1 H), 7.83 (br. s., 1 H), 7.76 (s, 1 H), 7.68 (br. s., 1H), 7.42 (d, 1 H), 4.90 (dd, 1 H), 4.71 (dd, 1 H), 4.43 (dd, 1 H), 4.04-4.14 (m, 1 H), 3.98 (s, 3 H), 1.89-2.09 (m, 1 H), 0.80-0.93 (m, 1 H),0.49-0.59 (m, 2 H), 0.24-0.37 (m, 2 H) 369

P1 L120 3, 7 374 ¹H NMR (400 MHz, dmso-d₆) δ 8.66 (s, 1 H), 8.18 (s, 1H), 7.92 (d, 1 H), 7.83 (br. s., 1 H), 7.70 (br. s., 1 H), 7.52 (s, 1H), 7.45 (d, 1 H), 5.23 (dd, 1 H), 4.51- 4.66 (m, 2 H), 4.06 (dt, 1 H),3.98 (s, 3 H), 1.96-2.14 (m, 1 H), 0.81-0.95 (m, 1 H), 0.46- 0.57 (m, 2H), 0.21-0.34 (m, 2 H) 370

P1 L121 3, 7 380 ¹H NMR (400 MHz, dmso-d₆) δ 8.85 (br. s., 1 H), 8.16(s, 1 H), 7.90 (d, 1 H), 7.83 (br. s., 1 H), 7.73 (s, 1 H), 7.68 (br.s., 1 H), 7.43 (d, 1 H), 4.92 (dd, 1 H), 4.62-4.71 (m, 1 H), 4.49-4.60(m, 2 H), 4.32 (dd, 1 H), 4.09- 4.18 (m, 1 H), 3.96 (s, 3 H), 2.77-2.96(m, 1 H), 1.92-2.08 (m, 2 H). 371

P23 17342- 08-4 commer- cial 3, 22, 16 (Ref. 37) 424 ¹H NMR (400 MHz,CD₃OD) δ 8.78 (s, 1 H), 8.00 (s, 1 H), 7.79 (s, 1 H), 7.77 (s, 1 H),7.39 (s, 1 H), 4.99 (dt, 1 H), 4.59 (dd, 1 H), 4.52 (dd, 1 H), 4.19-4.27(m, 1 H), 3.85 (s, 3 H), 2.36-2.58 (m, 3 H), 2.06-2.17 (m, 1 H), 1.50(t, 6 H) 372

P23 17342- 08-4 commer- cial 3, 22, 16 (Ref. 38) 438 ¹H NMR (400 MHz,CD₃OD) δ 8.76 (s, 1 H), 7.98 (s, 1 H), 7.77 (s, 1 H), 7.28 (s, 1 H),4.99 (dt, 1 H), 4.59 (dd, 1 H), 4.52 (dd, 1 H), 4.19-4.27 (m, 1 H), 3.73(s, 3 H), 2.47 (s, 3 H), 2.37-2.58 (m, 3 H), 2.07-2.18 (m, 2 H), 1.50(t, 6 H). 373

P23 17342- 08-4 commer- cial 3, 22, 16 (Ref. 39) 424 ¹H NMR (400 MHz,CD₃OD) δ 8.70 (s, 1 H), 7.99 (s, 1 H), 7.78 (s, 1 H), 7.27 (s, 1 H),5.00 (dt, 1 H), 4.61 (m, 1 H), 4.52 (dd, 1 H), 4.18-4.28 (m, 1 H), 2.51(s, 3 H), 2.36-2.60 (m, 3 H), 2.06- 2.17 (m, 1 H), 1.50 (t, 6 H) 374

P1 L123 3, 7 364 ¹H NMR (600 MHz, dmso-d₆) δ 8.79 (br. s., 1 H), 8.16(s, 1 H), 7.90 (d, 1 H), 7.80 (br. s., 1 H), 7.74 (s, 1 H), 7.63 (br.s., 1 H), 7.42 (d, 1 H), 4.55 (dd, 1 H), 4.27 (dd, 1 H), 4.04-4.12 (m, 1H), 3.97 (s, 3 H), 1.54-1.66 (m, 2 H), 1.02 (t, 3 H) 375

P1 L124 3, 7 366 ¹H NMR (400 MHz, dmso-d₆) δ 8.81 (s, 1 H), 8.65 (d, 1H), 8.20 (s, 1 H), 7.83 (br. s., 1 H), 7.68 (br. s., 1 H), 7.46 (s, 1H), 7.05 (d, 1 H), 5.33 (dd, 1 H) 4.86 (dd, 1 H), 4.74 (dd, 1 H),4.39-4.27 (m, 1 H), 4.24 (d, 2 H), 3.99 (s, 3 H), 3.26-3.06 (m, 1 H) 376

P23 17342- 08-4 commer- cial 3, 22, 16 (Ref 40) ¹H NMR (400 MHz, CD₃OD)δ 9.27 (s, 1 H), 8.79 (d, 1 H), 8.49 (s, 1 H), 7.80 (s, 1 H), 7.38 (d, 1H), 5.00 (dt, 1 H), 4.62-4.69 (m, 1 H), 4.53-4.62 (m, 1 H), 4.20-4.31(m, 1 H), 2.65 (s, 3 H), 2.38-2.58 (m, 3 H), 2.07- 2.19 (m, 1 H), 1.51(t, 6 H) 377

P23 17342- 08-4 commer- cial 3, 22, 16 (Ref 41) ¹H NMR (400 MHz, CD₃OD)δ 9.46 (s, 1 H), 8.97 (s, 2 H), 8.67 (s, 1 H), 7.81 (s, 1 H), 5.00 (dt,1 H), 4.62-4.72 (m, 1 H), 4.51- 4.62 (m, 1 H), 4.18-4.32 (m, 1 H),2.36-2.62 (m, 3 H), 2.04- 2.21 (m, 1 H), 1.51 (t, 6H) 378

P23 17342- 08-4 commer- cial 3, 22, 16 Ref. 42) ¹H NMR (400 MHz, CD₃OD)δ 8.36 (s, 1 H), 7.99 (s, 1 H), 7.82 (s, 1 H), 7.72 (dd, 1 H), 6.62 (d,1 H), 6.53 (d, 1 H), 5.01 (dt, 1 H), 4.61-4.70 (m, 1 H), 4.50- 4.60 (m,1 H), 4.18-4.30 (m, 1 H), 2.36-2.59 (m, 3 H), 2.06- 2.20 (m, 1 H), 1.50(t, 6 H) 379

P23 17342- 08-4 commer- cial 3, 22, 16 (Ref 43) ¹H NMR (400 MHz, CD₃OD)δ 8.85 (s, 1 H), 8.79 (d, 1 H), 8.17 (s, 1 H), 7.83 (s, 1 H), 7.63 (d, 1H), 5.02 (dt, 1 H), 4.62-4.71 (m, 1 H), 4.53-4.62 (m, 1 H), 4.21-4.31(m, 1 H), 2.80 (s, 3 H), 2.37-2.59 (m, 3 H), 2.05-2.18 (m, 1 H), 1.51(t, 6 H)

TABLE 1 REFERENCES AND NOTES

-   1. Organic Process Research and Development, 2011, 15, 1052-1062.-   2. European Journal of Organic Chemistry 2005, 1354-1366.-   3. Prepared as described in US patent application US 2012/95040 A1.-   4. Organic & Biomolecular Chemistry, 2005, 3, 603-611.-   5. Prepared as described in WPO patent application WO 2007125405 A2-   6. Prepared as described in US patent application US 2013/79324 A1.-   7. Korean Journal of Medicinal Chemistry, 1994, 4, 119-125.-   8. Organic Process Research and Development, 2011, 15, 1052-1062.-   9. Journal of Organic Chemistry, 1987, 52, 5247-5254.-   10. Prepared as described in US patent application US 2007/0265272    A1.-   11. Tetrahedron: Asymmetry 1995, 6, 1181-1190.-   12. Bioorganic and Medicinal Chemistry Letters 2010, 20, 4749-4752.-   13. Prepared as described in US patent application US 2012/95040 A1.-   14. Bioorganic and Medicinal Chemistry Letters 2011, 21, 3290-3296.-   15. Tetrahedron 2012, 68, 1286-1298.-   16. Prepared as described in World patent application WO 2013/042006    A1.-   17. Tetrahedron: Asymmetry 2004, 15, 1659-1665.-   18. Tetrahedron: Asymmetry, 2002, 13, 647-658.-   19. Prepared as described in World patent application WO 2008/128919    A2.-   20. Journal of Medicinal Chemistry 1987, 30, 992-998.-   21. Journal of the Chemical Society, Perkin Transactions 1, 2002,    1076-1082.-   22. Prepared as described in US patent application US 2010/197654    A1.-   23. Journal of the American Chemical Society 2010, 132, 1188-1189.-   24. Prostaglandins 1979, 17, 223-226.-   25. Organic Letters, 1999, 1, 2105-2107.-   26. Tetrahedron, 2007, 63, 10587-10595.-   27. Tetrahedron Letters, 1998, 39, 857-860.-   28. Prepared as described in European patent application EP 438311    A2.-   29. Journal of the American Chemical Society 1999, 121, 10478-10486.-   30. Journal of Medicinal Chemistry 1991, 34, 887-900.-   31. Journal of the Chemical Society, Perkin Transactions 1: Organic    and Bio-Organic Chemistry 1997, 2111-2122.-   32. Tetrahedron Letters 1989, 30, 6637-6640.-   33. Archiv der Pharmazie 1964, 297, 632-638.-   34. Canadian Journal of Chemistry 1956, 34, 815-820.-   35. Journal of Organic Chemistry, 1997, 62, 4770-4779.-   36.1H NMR (500 MHz, dmso-d₆) δ 8.28 (s, 1H, diastereomer 1),    8.18-8.22 (m, 1H, both diastereomers), 8.16 (s, 1H, diastereomer 2),    7.87-7.91 (d, 1H, both diastereomers), 7.74 (br. s., 1H, both    diastereomers), 7.71 (s, 1H, both diastereomers), 7.62 (br. s, 1H,    both diastereomers), 7.42 (d, 1H, both diastereomers), 4.92-5.01 (m,    1H, diastereomer 1), 4.86-4.93 (m, 1H, diastereomer 2), 4.56 (dd,    1H, diastereomer 1), 4.44-4.51 (m, 1H, diastereomer 2), 4.31-4.38    (m, 1H, diastereomer 1), 4.22 (dd, 1H, diastereomer 2), 3.93-4.05    (m, 1H, both diastereomers), 3.48-3.54 (m, 2H, both diastereomers),    3.27 (s, 3H, diastereomer 1), 3.26 (s, 3H, diastereomer 2),    2.69-2.80 (m, 1H, diastereomer 1), 2.61-2.68 (m, 1H, diastereomer    2), 2.33-2.43 (m, 1H, diastereomer 1), 2.21 (dt, 1H, diastereomer    2), 2.06-2.15 (m, 1H, diastereomer 1), 1.76 (dt, 1H, diastereomer    2), 1.35-1.45 (m, 6H, both diastereomers)-   37. 4-Bromo-1-methyl-1H-imidazole was used as the Suzuki coupling    partner in the step of Method 16.-   38. 4-Bromo-1,2-dimethyl-1H-imidazole was used as the Suzuki    coupling partner in the step of Method 16.-   39. Tert-butyl 4-bromo-2-methyl-1H-imidazole-1-carboxylate was used    as the Suzuki coupling partner in the step of Method 16.-   40. 2-Bromo-4-methylpyrimidine was used as the Suzuki coupling    partner in the step of Method 16.-   41. 2-Bromo-5-chloropyrimidine was used as the Suzuki coupling    partner in the step of Method 16.-   42. 6-Bromopyridin-2(1H)-one was used as the Suzuki coupling partner    in the step of Method 16.-   43. 4-Bromo-2-methylpyrimidine was used as the Suzuki coupling    partner in the step of Method 16.

Table 2 names some of the specific intermediates unique to this work. Asdescribed in Scheme 1, compounds such as P1, P16 or P3, P5, or P25,which may be prepared, respectively, from C5, C29 and C17, C25 and C179may undergo nucleophilic aromatic substitution reactions with alcoholsto afford products of the general structure 1a (See Scheme 1). Asdescribed in Scheme 2, compounds such as P5 or P25, which may beprepared, respectively, from C25 and C179, may undergo reactions such asalkylation or Mitsunobu reaction to afford products of the generalstructure 1a (See Scheme 2). As described in Scheme 10, α,β-unsaturatedlactams such as(S)-3,3-dimethyl-1,7α-dihydropyrrolo[1,2-c]oxazol-5(3H)-one (P20) may betreated with an organometallic reagent such as an alkyllithium or alkylGrignard reagent in the presence of chlorotrimethylsilane and a coppercompound. Some examples in the literature include reaction ofbenzylidene-protected lactams with alkyl or vinyl cuprate reagents toafford addition of analkyl or vinyl group anti to the existingstereocenter. For example, see: N. Okamoto et al., Tetrahedron Asymmetry2001, 12(9), 1353-1358. Hara et al., Tetrahedron 2004, 60(37),8031-8035; A. Endo and S. Danishefsky, J. Am. Chem. Soc. 2005,127(23),8298-8299. In the chemistry described herein using the acetonidederivative P20, conjugate addition generally occurs in an unprecedentedmanner to afford a product with the new substituent syn to the existingstereocenter. Representative conjugate addition products include C53,C54, C55, and C56. Such lactams may undergo further elaboration, forexample, to provide fluoro derivatives such as C53, C59, C61, and C62,or oxygenated derivatives such as C54.

TABLE 2 Intermediate Structure Name C5

7-methoxyisoquinoline-6-carbonitrile C28

1-chloro-7-hydroxyisoquinoline-6- carbonitrile P1

1-chloro-7-methoxyisoquinoline-6- carbonitrile C29

4-chloro-6-hydroxyquinoline-7- carbonitrile P16

4-chloro-6-methoxyquinoline-7- carbonitrile C17

6-methoxy-4-oxo-3,4- dihydroquinazoline-7-carbonitrile P3

4-chloro-6-methoxyquinazoline-7- carbonitrile C25

methyl 5-((tert-butyldiphenylsilyl)oxy)- 3-hydroxy-2-napthoate P5

5-hydroxy-3-methoxy-2-naphthamide C179

methyl 8-fluoro-5-hydroxy-3-methoxy- 2-naphthoate P25

8-fluoro-5-hydroxy-3-methoxy-2- naphthamide C53

(7R,7aS)-3,3,7- trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- one C54

(7R,7aS)-7-ethyl-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- oneC55

(7S,7aS)-3,3-dimethyl-7- vinyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-oneC56

(7S,7aS)-7-cyclopropyl-3,3- dimethyltetrahydropyrrolo[1,2-c]oxazo-5(3H)-one C58

(6R,7S,7aS)-6-fluoro-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- one C59

(6S,7S,7aS)-6-fluoro-3,3,7-trimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- one C61

(6S,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- one C62

(6R,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- one C54

(7S,7aS)-7-ethyl-6-hydroxy-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)- one L38

(3S,4S,5S)-3-fluoro-5-(hydroxymethyl)- 4-methylpyrrolidin-2-one L47

(4R,5S)-4-ethyl-5- (hydroxymethyl)pyrrolidin-2-one L74

(1R,4S,5S,6S)-4-(hydroxymethyl)-6- methyl-3-azabicyclo[3.1.0]hexan-2-oneL54

(3S,4S,5S)-4-ethyl-3-fluoro-5- (hydroxymethyl)pyrrolidin-2-one L61

(4R,5S)-3-fluoro-5-(hydroxymethyl)-4- (methoxymethyl)pyrrolidin-2-oneL68

(4S,5S)-3-(benzyloxy)-4-ethyl-5- (hydroxymethyl)pyrrolidin-2-one L116

(4S,5S)-4-(2-fluoroethyl)-5- (hydroxymethyl)pyrrolidin-2-one L118

(3S,4R,5S)-3-fluoro-4-(fluoromethyl)-5- (hydroxymethyl)pyrrolidin-2-oneL121

(3S,4S,5S)-3-fluoro-4-(2-fluoroethyl)-5- (hydroxymethyl)pyrrolidin-2-oneL124

(3R,4R,5S)-3-fluoro-4-(fluoromethyl)-5- (hydroxymethyl)pyrrolidin-2-one

Biological Activity:

IRAK4 Enzymatic DELFIA Assay, Protocol A.

This is an in vitro assay to measure IRAK4 enzymatic activity utilizingthe DELFIA (Dissociation-Enhanced Lanthanide Fluorescent Immunoassay,Perkin-Elmer) platform, with the human IRAK4 FL (Full Length) constructto characterize IRAK4 inhibitor and control compounds at 0.6 mM ATP(K_(M)). The final amount of enzyme in the assay is 0.1 nM IRAK4 FL,final concentration of substrate is 50 nM, and final concentration ofDMSO is 2.5%.

The test compound was solubilized in DMSO to a stock concentration of 30mM. The dose response plates were prepared with a 4 mM primary compoundconcentration, and then diluted in DMSO in a four-fold series for atotal of 11 data points. Compounds were prepared as a 40-fold multipleof the final in-assay concentration.

To begin the assay, 19 μL of reaction mixture containing 20 mM HEPESpH=7.5, 5 mM MgCl₂, 0.0025% Brij-35, 600 μM ATP, 0.21 nM Full-lengthphosphorylated recombinant human IRAK4 (GenBank ID AF445802) werealiquoted into Ultra-Clear Polypropylene, 384-well, U-Bottom Plates(Corning Life Sciences). 1 μL of test compound from the dose-responseplate was added to the reaction mixture and incubated for 20 minutes atroom temperature. Then 20 μL of 20 mM HEPES pH=7.5, 5 mM MgCl₂, 0.0025%Brij-35, 600 μM ATP, and 100 nM ERM-biotinylated peptide(AGAGRDKYKTLRQIR) was added to start the reaction. The reaction wasincubated for 60 minutes at room temperature and stopped by the additionof 20 μL 0.3M EDTA.

50 μL of the reaction mixture was transferred to a streptavidin coateddetection plate (DELFIA streptavidin coated plates, 384-well, whiteplates, Perkin-Elmer Life Sciences) and incubated for 30 minutes at roomtemperature. The plates were washed 4x with 75 μL per well of PBScontaining 0.05% Tween-20. Plates were then incubated with 50 μL perwell of antibody cocktail of Anti-pERM antibody at 0.125 μg/mL (CellSignaling Technology), plus Anti-Rabbit IgG EuN1 at 0.25 ug/ml(Perkin-Elmer Life Sciences) in a solution of 10 mM MOPS pH=7.5, 150 mMNaCl, 0.05% Tween-20, 0.02% NaN₃, 1% BSA, 0.1% Gelatin for 45 minutes.The plates were washed 4x with 50 μL per well of PBS containing 0.05%Tween-20. Then 50 μL per well of DELFIA Enhancement Solution(Perkin-Elmer Life Sciences) were added to the plate and then read on anEnVision Model 2103 using a 340 nm excitation wavelength and a 665 nmemission wavelength for detection.

IRAK4 Enzymatic DELFIA Assay, Protocol B.

This is an in vitro assay to measure IRAK4 enzymatic activity utilizingthe DELFIA (Dissociation-Enhanced Lanthanide Fluorescent Immunoassay,Perkin-Elmer) platform, with the human IRAK4 kinase domain (aa 154-460)construct to characterize IRAK4 inhibitor and control compounds at 0.6mM ATP (K_(M)). The final amount of enzyme in the assay is 114 μM IRAK4kinase domain, final concentration of substrate is 200 nM, and finalconcentration of DMSO is 5%.

The test compound was solubilized in DMSO to a stock concentration of 30mM. The dose response plates were prepared with a 2 mM primary compoundconcentration, and then diluted in DMSO in a four-fold series for atotal of 10 data points. Compounds were prepared as a 20-fold multipleof the final in-assay concentration

To begin the assay, 45 μL of reaction mixture containing 20 mM HEPESpH=7.5, 5 mM MgCl₂, 0.0025% Brij-35, 600 μM ATP, 228 μM phosphorylatedrecombinant human IRAK4 kinase domain (aa 154-460; GenBank ID AF445802)were aliquoted into Ultra-Clear Polypropylene, 96-well, U-Bottom Plates(Corning Life Sciences). 5 μL of test compound from the dose-responseplate was added to the reaction mixture and incubated for 15 minutes atroom temperature. Then 50 μL of 20 mM HEPES pH=7.5, 5 mM MgCl₂, 0.0025%Brij-35, 600 μM ATP, and 400 nM ERM-biotinylated peptide(AGAGRDKYKTLRQIR) were added to start the reaction. The reaction wasincubated for 90 minutes at room temperature and stopped by the additionof 25 μL 0.5M EDTA.

100 μL of the reaction mixture was transferred to a streptavidin coateddetection plate (EvenCoat Streptavidin Coated Plates, 96-Well, R&DSystems) and incubated for 30 minutes at room temperature. The plateswere washed 4 times with 100 μL per well of PBS containing 0.05%Tween-20. Plates were then incubated with 50 μL per well of antibodycocktail of Anti-pERM antibody (Cell Signaling Technology) diluted1:5000, plus Anti-Rabbit IgG EuN1 at 0.242 μg/ml (Perkin-Elmer LifeSciences) in a solution of 10 mM MOPS pH=7.5, 150 mM NaCl, 0.05%Tween-20, 0.02% NaN₃, 1% BSA, 0.1% Gelatin for 45 minutes. The plateswere washed 4x with 100 μL per well of PBS containing 0.05% Tween-20.Then 100 μL per well of DELFIA Enhancement Solution were added to theplate and then read on an EnVision Model 2103 using a 340 nm excitationwavelength and a 665 nm emission detection.

R848 Induced TNFα in Human PBMC Assay.

This protocol is for R848-induced TNFα production by human peripheralblood mononuclear cells (PBMCs). R848 is a synthetic agonist for theendosomal Toll-like receptors TLR7 and TLR8, which signal throughinterleukin-1 receptor-associated kinase 4 (IRAK4). The assay is used toassess cell-based potency of small molecule inhibitors of IRAK4 in theabsence of serum.

Peripheral blood mononuclear cells (PBMC) were purified from fresh humanblood by separation on a Histopaque-1077 cushion usingACCUSPIN-System-Histopaque-1077 system (Sigma Aldrich). Briefly, 30 mLof human blood were added to an ACCUSPIN tube containing 15 mL ofHistopaque-1077 and spun for 20 minutes at 1200×g at room temperature inan Eppendorf 5804R swinging-bucket centrifuge with low brake. The PBMCsin the interphase layer were collected and washed with PBS viacentrifugation multiple times until the supernatant is clear. Thepurified PBMCs were re-suspended in RPMI (Roswell Park MemorialInstitute) media (Sigma-Aldrich).

For the assay, a compound dilution plate containing a top concentrationof 4 mM compound in DMSO was serially diluted 4-fold for 11 times. 250nL of the compound dilution plate was spotted into a 384-well, flatbottom with lid, TC-treated, black with clear bottom, sterile,polystyrene plate (Corning Life Sciences). 100,000 PBMCs in 50 μL ofRPMI containing 5.5 μM R⁸⁴⁸ are added to each well of the 384 well plateand allowed to incubate for 3 hours at 37° C.

Plates were briefly spun at 1200×g Eppendorf 5804R swinging-bucketcentrifuge for 5 minutes and 15 μL of the supernatant from each well istransferred to the corresponding well of a Human TNFα 384-Well TissueCulture MSD Kit (Mesoscale Discovery). 10 μL of anti-TNFα antibodylabeled with MSD SULFO-TAG at 50 μg/mL was added to each well andallowed to incubate overnight at 4° C. The plates were then washed with1×PBS containing 0.05% Tween 20 after which 35 μL of MSD read buffer T(Mesoscale Discovery) was added to each well. The plates were thenimaged on an MSD Sector Imager 6000.

TABLE 3 Biological Activity IRAK4 IRAK4 R848- DELFIA DELFIA inducedProtocol A Protocol B TNFa PBMC Ex. # IC50 (nM) IC50 (nM) IC50 (nM)IUPAC NAME 1 29134-(azetidin-3-ylmethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 24497 4-[(3S)-piperidin-3-ylmethoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 3 22394-[(3R)-piperidin-3-ylmethoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 4 9134-(piperidin-4-ylmethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 5323 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 6 6184-(oxetan-3-ylmethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 7 1704-(cyclopentylmethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 8 8344-(1-cyclobutylethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 9 5984-(cyclobutylmethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 10 7526-(propan-2-yloxy)-4-(tetrahydrofuran-3-ylmethoxy)quinoline-7-carboxamide 11 32346-(propan-2-yloxy)-4-(tetrahydrofuran-2-ylmethoxy)quinoline-7-carboxamide 12 10424-[(3-methyloxetan-3-yl)methoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 13 3834-[(1-methylcyclobutyl)methoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 14 2314-[(2R)-bicyclo[2.2.1]hept-2-yloxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 15 29696-(propan-2-yloxy)-4-[(2R)-tetrahydrofuran-2-ylmethoxy]quinoline-7-carboxamide 16 3864-(bicyclo[2.2.1]hept-2-yloxy)-6-(propan-2-yloxy)quinoline-7-carboxamide 17 4766-(propan-2-yloxy)-4-(tricyclo[2.2.1.0~2,6~]hept-3-yloxy)quinoline-7-carboxamide 18 5074-(1,3-dioxolan-4-ylmethoxy)-6-(propan-2- yloxy)quinoline-7-carboxamide19 354 4-[(1S,2R)-bicyclo[2.2.1]hept-2-yloxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 20 1021-[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-4-yloxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 21 834-[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-4-yloxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 22 454-{[(3S)-1-(cyanoacetyl)pyrrolidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 23 6564-{[(3R)-1-(cyanoacetyl)pyrrolidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 24 4927-(propan-2-yloxy)-1-(tetrahydrofuran-3-ylmethoxy)isoquinoline-6-carboxamide 25 11307-(propan-2-yloxy)-1-(tetrahydro-2H-pyran-2-ylmethoxy)isoquinoline-6-carboxamide 26 4.6 1331-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 27 24831-[(1,1-dioxido-1,2-thiazinan-3-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 28 13201-[(3S)-piperidin-3-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 29 761-[(3-methyl-2-oxo-1,3-oxazolidin-4-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 30 24457-(propan-2-yloxy)-1-[(2R)-tetrahydrofuran-2-ylmethoxy]isoquinoline-6-carboxamide 31 26161-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 32 8401-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 33 28621-[(1-acetylpiperidin-4-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 34 4831-{[(3R,4R)-4-methoxypyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 35 161-[(2-oxo-1,3-oxazolidin-5-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 36 7357-(propan-2-yloxy)-1-(tetrahydro-2H-pyran-4-ylmethoxy)isoquinoline-6-carboxamide 37 35161-[(2S)-morpholin-2-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 38 46401-[(4-fluoropiperidin-4-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 39 3861-(morpholin-2-ylmethoxy)-7-(propan-2- yloxy)isoquinoline-6-carboxamide40 109 1-[(1S,5S)-3-azabicyclo[3.1.0]hex-1-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 41 23517-(propan-2-yloxy)-1-[(2R)-pyrrolidin-2-ylmethoxy]isoquinoline-6-carboxamide 42 2191-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 43 33231-(piperidin-2-ylmethoxy)-7-(propan-2- yloxy)isoquinoline-6-carboxamide44 4265 1-[(4-methylmorpholin-2-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 45 19221-[(1-methylpiperidin-3-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 46 2377-(propan-2-yloxy)-1-{[(3R,4R)-4-(trifluoromethyl)pyrrolidin-3-yl]methoxy}isoquinoline-6- carboxamide 472786 1-[(2R)-morpholin-2-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 48 3661-[(3R)-piperidin-3-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 49 4517-(propan-2-yloxy)-1-[(3S)-pyrrolidin-3-ylmethoxy]isoquinoline-6-carboxamide 50 7016-(propan-2-yloxy)-4-[(3S)-pyrrolidin-3-ylmethoxy]quinoline-7-carboxamide 51 24124-[(2S)-morpholin-2-ylmethoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 52 42364-(7-azaspiro[3.5]non-1-yloxy)-6-(propan-2-yloxy)quinoline-7-carboxamide 53 23804-[(2R)-morpholin-2-ylmethoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 54 24354-[(4-fluoropiperidin-4-yl)methoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 55 2644-{[(3R,4R)-3,4-dimethylpyrrolidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 56 14894-[(4-methylpiperidin-4-yl)methoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 57 5.84-{[(5R)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 58 1444-[(3-methylpiperidin-3-yl)methoxy]-6-(propan-2-yloxy)quinoline-7-carboxamide 59 2434-(piperidin-3-ylmethoxy)-6-(propan-2-yloxy)quinoline-7- carboxamide 608.9 4-{[1-(cyanoacetyl)azetidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 61 2491-{[(2R)-1-(cyanoacetyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 62 12861-{[1-(cyanoacetyl)piperidin-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 63 2521-{[(2S)-1-(cyanoacetyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 64 6411-{[(3R)-4-(cyanoacetyl)morpholin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 65 5631-({1-[(cyanoacetyl)amino]cyclopentyl}methoxy)-7-(propan-2-yloxy)isoquinoline-6-carboxamide 66 2551-{[(3S)-1-(cyanoacetyl)pyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 67 17301-{[(3R)-1-(cyanoacetyl)piperidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 68 3201-{[(1R,5R,6R)-3-(cyanoacetyl)-3-azabicyclo[3.2.1]oct-6-yl]oxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 69 291-{[1-(cyanoacetyl)azetidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 70 4231-{[(3R)-1-(cyanoacetyl)pyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 71 153 4-{[(3aR,6aS)-2-(cyanoacetyl)octahydrocyclopenta[c]pyrrol-4-yl]oxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 72 26251-[(1S,4R)-2-azabicyclo[2.2.1]hept-6-yloxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 73 11611-{[(2S)-1-(cyanoacetyl)azetidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 74 431-{[(1S,4S,5S)-2-(cyanoacetyl)-2-azabicyclo[2.2.1]hept-5-yl]oxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 75 40391-{[(2S)-4-(cyanoacetyl)morpholin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 76 17211-{[1-(cyanoacetyl)-4-fluoropiperidin-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 77 4681-{[(1S,5S)-3-(cyanoacetyl)-3-azabicyclo[3.1.0]hex-1-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 78 47431-{[(2R)-4-(cyanoacetyl)morpholin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 79 457 1-{[(3aR,4S,6aS)-2-(cyanoacetyl)octahydrocyclopenta[c]pyrrol-4-yl]oxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 80 3331-{[(3R,4R)-1-(cyanoacetyl)-4-ethylpyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 81 4791-{[(1S,5S,6S)-3-(cyanoacetyl)-3-azabicyclo[3.2.1]oct-6-yl]oxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 82 9691-{[1-(cyanoacetyl)-3-methylpyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 83 1751-{[(3S)-4-(cyanoacetyl)morpholin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 84 5341-{[(3R,4R)-1-(cyanoacetyl)-4-methoxypyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 85 6101-{[(3R,4R)-1-(cyanoacetyl)-4-methylpyrrolidin-3-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 86 2161-{[1-(cyanoacetyl)-4-methylpiperidin-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 87 26214-{[(1R,5S,6r)-3-(cyanoacetyl)-3-azabicyclo[3.1.0]hex-6-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 88 2924-{[(3R,4R)-1-(cyanoacetyl)-4-methylpyrrolidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 89 3954-{[(1R,5R,6R)-3-(cyanoacetyl)-3-azabicyclo[3.2.1]oct-6-yl]oxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 90 4384-{[(1S,5S)-3-(cyanoacetyl)-3-azabicyclo[3.1.0]hex-1-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 91 4894-{[1-(cyanoacetyl)-4-methylpiperidin-4-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 92 4734-{[(1S,5S,6S)-3-(cyanoacetyl)-3-azabicyclo[3.2.1]oct-6-yl]oxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 93 15204-{[(3S)-1-(cyanoacetyl)piperidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 94 5264-{[(1S,5S)-3-(cyanoacetyl)-3-azabicyclo[3.1.0]hex-1-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 95 31674-{[1-(cyanoacetyl)-4-fluoropiperidin-4-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 96 3014-{[(3R,4R)-1-(cyanoacetyl)-4-methoxypyrrolidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 97 27414-{[(3R)-1-(cyanoacetyl)piperidin-3-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 98 5754-{[(2S)-4-(cyanoacetyl)morpholin-2-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 99 5244-{[1-(cyanoacetyl)piperidin-2-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 100 4824-{[1-(cyanoacetyl)piperidin-4-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 101 11771-[(1S,4S,5S)-2-azabicyclo[2.2.1]hept-5-yloxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 02 2171-[(1R,4R,5R)-2-azabicyclo[2.2.1]hept-5-yloxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 03 575 27411-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carbonitrile 04 6.6 17961-{[(4R)-2-oxo-1,3-oxazolidin-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 05 844-methyl-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 06 51 4721-{[(2S)-6-oxopiperidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 107 161-{[(2S)-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 108 18671-[(1S,4R,6R)-2-azabicyclo[2.2.1]hept-6-yloxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 109 19091-[(1S,4R,6S)-2-azabicyclo[2.2.1]hept-6-yloxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 110 418 11671-{[(2S)-4,4-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 111 1961-[(5-oxopyrrolidin-3-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 112 1 501-{[(2S)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 113 531-{[(2S)-4-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 114 0.7 335-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-3-(propan-2-yloxy)naphthalene-2-carboxamide 115 613-(propan-2-yloxy)-5-[(3R)-pyrrolidin-3-ylmethoxy]naphthalene-2-carboxamide 116 1461-[(5-oxomorpholin-3-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 117 1367-(propan-2-yloxy)-1-[(3R)-pyrrolidin-3-ylmethoxy]isoquinoline-6-carboxamide 118 1621-[(3-oxooctahydro-1H-isoindol-1-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 119 14291-[(2S)-azetidin-2-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 120 11417-(cyclobutyloxy)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 121 7.6 3477-methoxy-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 122 24 6727-ethoxy-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 123 7471-[(3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(1H)-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 124 7.8 1751-{[(2S,4R)-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 125 40 6851-{[(2S,4S)-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 126 421-{[(2S)-2-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 127 65 6821-{[(2S)-4-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 128 0.3 271-{[(2S)-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 129 2317-(difluoromethoxy)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 130 4171-{[(3aS,6R,6aR)-2-oxooctahydrocyclopenta[b]pyrrol-6-yl]oxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 131 0.6 291-{[(2S,4S)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 132 188 11801-{[(2S,4R)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 133 1751-{[(2S,4R)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 134 1 361-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 135 1.2 321-{[(2S,4S)-4-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 136 7.8 1841-{[(2S,4R)-4-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 137 981-{[(2S,4R)-4-(2-hydroxypropan-2-yl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 138 10371-[(2-oxopiperidin-4-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 139 2561-[(1S,5S)-3-azabicyclo[3.1.0]hex-1-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 140 841-[(1R,5R)-3-azabicyclo[3.1.0]hex-1-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 141 70 2941-{[(2S,3S)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 142 12221-[(6-oxopiperidin-3-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 143 25421-[(1,1-dioxido-1,2-thiazolidin-3-yl)methoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 144 1.4 1411-{[(2S,4R)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 145 0.4 411-{[(2S,4S)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 146 0.2 151-{[(2S)-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 147 59 11611-{[2-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 148 241-{[(2S)-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 149 1051-{[(2S,3S)-3-amino-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 150 41 8641-{[(2S,4S)-4-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 151 1.2 251-{[(2S,4S)-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 152 6.7 1391-{[(2S,4R)-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 153 14801-{[(2S)-2-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 154 171-{[(2R)-2-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 155 2671-{[(2S,3S)-5-oxo-3-(trifluoromethyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 156 40971-{(1R)-1-[(2S)-5-oxopyrrolidin-2-yl]ethoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 157 1521-{(1S)-1-[(2S)-5-oxopyrrolidin-2-yl]ethoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 158 14431-[(3R)-morpholin-3-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 159 33777-(propan-2-yloxy)-1-(pyrrolidin-2- ylmethoxy)isoquinoline-6-carboxamide160 151 1-[(3S)-morpholin-3-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 161 881-[(1R,6S)-3-azabicyclo[4.1.0]hept-1-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 162 351-[(1S,6R)-3-azabicyclo[4.1.0]hept-1-ylmethoxy]-7-(propan-2-yloxy)isoquinoline-6-carboxamide 163 1396 74491-{[(2S,4S)-4-fluoro-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 164 1.7 1161-{[(2S,4R)-4-fluoro-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 165 5411-{[(2S,4R)-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 166 4.3 3891-{[(2S,4S)-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 167 191-{[(3aR,4R,6aR)-2,2-dimethyl-6-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 168 6.6 14564-fluoro-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 169 8901-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxylic acid 170 0.8 411-{[(2S,3S,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 171 1011-{[(2S,4R)-4-fluoro-4-(2-hydroxypropan-2-yl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 173 1.3 37 3-methoxy-5-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}naphthalene-2-carboxamide 174 3.1 1261-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 175 1011-{[(1S,5S)-4-oxo-3-azabicyclo[3.1.0]hex-1-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 176 6958-fluoro-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 177 3.8 431-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 178 16891-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(trifluoromethoxy)isoquinoline-6-carboxamide 179 1.2 1991-{[(2S,4R)-4-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 180 1786 25551-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 181 5.7 5031-{[(2S)-4-(4-hydroxytetrahydro-2H-pyran-4-yl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 182 1048 1-{[(2S,4R)-4-hydroxy-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 183 0.2 101-{[(2S,3S)-4,4-difluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 184 601-{[(2S,4S)-4-hydroxy-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 185 1161-{[(4S)-1-methyl-2-oxoimidazolidin-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 186 3031-{[(5S,6R)-2-oxo-1-azaspiro[4.4]non-6-yl]oxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 187 1.1 401-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 188 1.9 301-{[(2S,3S,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 189 0.3 121-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 190 2944-cyano-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 191 2527-(propan-2-yloxy)-1-(pyrrolidin-3- ylmethoxy)isoquinoline-6-carboxamide192 284 1-{[(2S,4R)-4-(3-hydroxyoxetan-3-yl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 193 2381-{[(2S,4S)-4-(3-hydroxyoxetan-3-yl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 194 1 5.25-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide 195 34024-(aminomethyl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 196 111-{[(2R,3R,4S)-3-ethyl-4-fluoro-3-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 197 711-{[(3S,4S)-3-ethyl-4-fluoro-2-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 198 7151-{[(2S,3R,4S)-4-fluoro-3-(1-hydroxyethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 1992904 7-(oxetan-3-yloxy)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 200 6977-tert-butoxy-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 201 0.4 11-{[(2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 202 85 9221-{[(4S)-2-oxoimidazolidin-4-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 203 3.5 471-{[(2S,3R,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 204 20647-(cyclopropylmethoxy)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 205 3.6 3801-{[(2S,4R)-4-fluoro-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 206 216 45706-methoxy-4-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-7-carboxamide 207 415-{[(2S,4R)-4-fluoro-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide 208 1.1 871-{[(2S,3S,4R)-4-fluoro-4-(hydroxymethyl)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 209 2519309 6-methoxy-4-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}quinazoline-7-carboxamide 210 34671-{[(2S,3S,4S)-4-fluoro-4-(hydroxymethyl)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 211 2.752 7-methoxy-1-{[(2S,3R)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 212 1501-{[(2S,3S)-3-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 213 14161-{[(1S,3aS,6aR)-5-methyl-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6- carboxamide 214215 1-{[(2S,3S)-3-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 215 1.7 351-{[(2S,4S)-4-fluoro-4-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 216 0.4 273-methoxy-5-{[(2S,3R)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}naphthalene-2-carboxamide 218 0.3 115-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide 219 1.7 651-{[(2S,3R)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 220 0.9 148-fluoro-5-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2- carboxamide 221 541-{[(2S)-3,3-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 222 18701-{[(2R)-3,3-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 223 151-{[(2R)-3,3-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 224 11731-{[(2S,4R)-4-(cyanomethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 225 3.4 1551-{[(2S,4S)-4-(cyanomethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 226 2221-{[(1S,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 227 19 7497-methoxy-1-{[(4R,5R)-5-methyl-2-oxo-1,3-oxazolidin-4-yl]methoxy}isoquinoline-6-carboxamide 228 4.2 1183-methoxy-5-{[(4R,5R)-5-methyl-2-oxo-1,3-oxazolidin-4-yl]methoxy}naphthalene-2-carboxamide 229 3514 62987-methoxy-1-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methoxy}isoquinoline-6-carboxamide 230 7 1997-methoxy-1-{[(4R)-2-oxo-1,3-oxazolidin-4-yl]methoxy}isoquinoline-6-carboxamide 231 67 5093-methoxy-5-{[(2S,4S)-4-methoxy-5-oxopyrrolidin-2-yl]methoxy}naphthalene-2-carboxamide 232 20 2613-methoxy-5-{[(2S,4R)-4-methoxy-5-oxopyrrolidin-2-yl]methoxy}naphthalene-2-carboxamide 233 0.3 473-methoxy-5-{[(4R)-2-oxo-1,3-oxazolidin-4-yl]methoxy}naphthalene-2-carboxamide 234 1.9 453-methoxy-5-{[(4R,5S)-5-methyl-2-oxo-1,3-oxazolidin-4-yl]methoxy}naphthalene-2-carboxamide 235 97 10927-methoxy-1-{[(5R)-2-oxo-1,3-oxazolidin-5-yl]methoxy}isoquinoline-6-carboxamide 236 8.4 1257-methoxy-1-{[(4R,5S)-5-methyl-2-oxo-1,3-oxazolidin-4-yl]methoxy}isoquinoline-6-carboxamide 237 295 10761-{[(2S,3S,4R)-4-fluoro-3,4-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 238 3.7 451-{[(2S,3S,4S)-4-fluoro-3,4-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 239 11827-methoxy-1-{[(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}isoquinoline-6-carboxamide 240 2.3 245-{[(2S,4R)-4-fluoro-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide 241 161 5765 5-{[(2S,4S)-4-fluoro-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide 242 263 72487-methoxy-1-{[(2S,4S)-4-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 243 205 7137-methoxy-1-{[(2S,4R)-4-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 244 4.7 641-{[(2S,3S)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 245 29 5297-methoxy-1-{[(6S)-4-oxo-5-azaspiro[2.4]hept-6-yl]methoxy}isoquinoline-6-carboxamide 246 0.5 91-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 247 29 28361-{[(2S,3R,4S)-3,4-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 248 3.7 871-{[(2S,3R,4R)-3,4-dimethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 249 20 7641-{[(2S,3S)-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 250 0.6 1444-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 251 3.4 721-{[(2S,3S)-3-ethenyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 252 0.9 401-{[(2S,4S)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 253 2.6 1221-{[(2S,4R)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 254 29511-{[(2S,3S,4S)-3-(fluoromethyl)-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 2551683 11527 7-methoxy-1-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 256 2000 56171-{[(2S,4R)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 257 6.8 601-{[(2S,4S)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 258 141 29331-{[(2S)-4-benzyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 259 3.1 1204-{[(2S,4S)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 260 202 62754-{[(2S,4R)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 261 6711-{[(2S,4R)-4-fluoro-4-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 262 4.7 16046-methoxy-4-{[(2S)-5-oxopyrrolidin-2- yl]methoxy}quinoline-7-carboxamide263 80 496 1-{[(1R,2S,5S)-6,6-dimethyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide264 4.8 115 7-methoxy-1-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 265 15397-methoxy-1-[(3-methyl-5-oxomorpholin-3-yl)methoxy]isoquinoline-6-carboxamide 266 74 3947-methoxy-1-[(4-methyl-2-oxo-1,3-oxazolidin-4-yl)methoxy]isoquinoline-6-carboxamide 267 15 1587-methoxy-1-{[(2S,4S)-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 2681.4 175 4-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 269 0.6 1044-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide 270 2907-methoxy-1-{[(2S,4R)-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 2712.4 52 7-methoxy-1-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 272 4322470 1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carbonitrile 73 4365 15861-(cyclopentylmethoxy)-7-methoxyisoquinoline-6- carboxamide 274 2.2 7484-{[(2S,4R)-4-fluoro-4-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 275 119 51371-{[(2R,4R)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 276 4.1 1071-{[(2S,4R)-4-fluoro-4-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 277 289 44207-methoxy-1-{[(2R,3S)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 278 8.5 2997-ethoxy-1-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 279 1.2 2126-ethoxy-4-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}quinoline-7-carboxamide 280 37896-ethoxy-4-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}quinoline-7-carboxamide 281 11 1277-(cyclopropyloxy)-1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 282 11 1917-ethoxy-1-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 283 1 277-ethoxy-1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 284 18 3201-{[(2S,4R)-4-fluoro-5-oxo-4-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 285 1531056 7-methoxy-1-(((1R,2S,5R,6R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)isoquinoline-6- carboxamide 286 1377025 7-methoxy-1-{[(2S,4S)-5-oxo-4-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 287 7.7 23026-ethoxy-4-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}quinoline-7-carboxamide 288 34 18091-{[(2R,3R,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 289 562 62711-{[(2S,4S)-4-(4-hydroxytetrahydro-2H-pyran-4-yl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 2901200 7-methoxy-1-{[(2S)-4-(oxetan-3-ylidene)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 291 326-ethoxy-4-{[(2S)-5-oxopyrrolidin-2- yl]methoxy}quinoline-7-carboxamide292 78 3136 1-{[(2S,4R)-4-fluoro-4-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 293 1.1 4626-ethoxy-4-{[(2S,4S)-4-fluoro-4-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}quinoline-7-carboxamide 294 3.3 247-ethoxy-1-{[(2S,4S)-4-fluoro-4-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 295 7.3 677-methoxy-1-{[(1S,2S,5R)-1-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 296 0.2 2.41-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 297 365 71257-methoxy-1-{[(1S,2S,5R)-5-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 298 12437-methoxy-1-{[(2S,4S)-4-(oxetan-3-yl)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 299 4.3 491-{[(1S,2S,5R)-1-ethyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 300 75 9311-{[(1S,2S,5R)-6-ethyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 301 338 40471-(((1R,2S,5R,6R)-6-ethyl-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide 302 28 1275 7-methoxy-1-{[(2S)-6-oxopiperidin-2-yl]methoxy}isoquinoline-6-carboxamide 303 127 60471-(((1S,2S,5S,6R)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide 304 1.3 35 1-{[(1R,2S,5S)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide305 2 57 1-{[(2S,3S)-3-cyclopropyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 306 155 40581-(((1R,2S,5R,6R)-6-(2-fluoroethyl)-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide 307 20607-methoxy-1-{[(1R,2S,5S)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 308 9.8 1347-methoxy-1-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.2.0]hept-2-yl]methoxy}isoquinoline-6-carboxamide 309 0.6 171-{[(1R,2S,5S)-5-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide310 10 380 1-(((1S,2S,5S,6R)-5-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide 311 229 1083 1-{[(1S,2S,5R)-6,6-dichloro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide312 1.3 26 7-methoxy-1-{[(2S,3R)-5-oxo-3-propylpyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 313 210 15937-methoxy-1-{[(1S,2S,5S)-6-(methoxymethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 314 19808356 7-methoxy-1-{[(1S,2S,5S)-6-(methoxymethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 315 1.5 451-{[(1S,2S,5R)-6-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 316 129 4644-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 317 0.6 221-{[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 318 1938 171881-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(prop-2-yn-1-yloxy)isoquinoline-6-carboxamide 319 1948 109901-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propadienyloxy)isoquinoline-6-carboxamide 320 0.8 111-{[(1R,2S,5S)-6-(difluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide321 4188 3-chloro-6-methoxy-4-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}quinoline-7-carboxamide 322 6.1 261-{[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.2.0]hept-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 323 0.2 304-{[(1R,2S,5S)-5-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7- carboxamide 3240.6 277 4-{[(1S,2S,5R)-6-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 325 0.4 874-{[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide 326 1.2 11966-methoxy-4-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}quinoline-7-carboxamide 327 20 33071-{[(1S,2S,5S)-6-(hydroxymethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide328 93 1-{[(1S,2S,5S)-6-(hydroxymethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide329 13 252 1-{[(2S,3R)-3-ethenyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 330 14 1347-methoxy-1-{[(4S)-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}isoquinoline-6-carboxamide 333 0.3 1824-{[(1R,2S,5S)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7- carboxamide 3344.2 1771 1-(((1R,2S,5R,6R)-6-fluoro-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide 335 4 746 1-{[(1S,2S,5R)-6-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide336 0.3 674 1-{[(1S,2S,5R)-6-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide337 0.1 6.5 1-{[(2S,3S,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 338 0.2 31-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-[(trideutero)methyloxy]isoquinoline-6-carboxamide 339 90269 1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(2-methoxyethoxy)isoquinoline-6-carboxamide 340 12 4567-methoxy-1-{[(2S,3R)-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 341 0.3 164-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinazoline-7-carboxamide 342 1003 23821-{[(2S,3S,4S)-3-ethyl-4-methoxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 343 41 4081-{[(2S,3S,4R)-3-ethyl-4-methoxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 344 0.2 0.51-{[(2S,3S,4S)-3-(pentadeutero)ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 345 0.21.6 1-{[(2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 346 6.1 1501-{[(2S,3R,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 347 0.6 271-{[(2S,3R)-4,4-difluoro-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 348 0.742 1-{[(2S,3R,4S)-4-fluoro-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 3492962 9461 7-methoxy-1-{[(2S,3S,4S)-4-methoxy-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 350 58 5687-methoxy-1-{[(2S,3S,4R)-4-methoxy-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 351 6.3 2131-{[(2S,3R,4R)-4-fluoro-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide 352 3.3557 1-{[(2S,3S,4S)-3-ethyl-4-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 353 0.5 201-{[(2S,3S,4R)-3-ethyl-4-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 354 28877-methoxy-1-{(1S)-1-[(2S)-5-oxopyrrolidin-2-yl]ethoxy}isoquinoline-6-carboxamide 355 1.7 331-{[(2S,3S)-3-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 356 115 5941-{[(2S,3R,4S)-4-amino-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 357 30 5881-{[(2S,3R,4R)-4-amino-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 358 0.4 1.31-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 359 0.4 3.97-ethoxy-1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide 360 0.1 3.91-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-4-fluoro-7-methoxyisoquinoline-6-carboxamide 361 4.8 271-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-8-fluoro-7-methoxyisoquinoline-6-carboxamide 362 1.1 281-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-4-fluoro-7-methoxyisoquinoline-6-carboxamide 363 11 1101-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-8-fluoro-7-methoxyisoquinoline-6-carboxamide 364 16 1454-fluoro-7-methoxy-1-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 365 187 7248-fluoro-7-methoxy-1-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide 366 6.1 911-{[(2S,3R)-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 367 0.4 141-{[(2S,3R,4S)-4-fluoro-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 368 0.3 101-{[(2S,3S,4S)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 369 3.7 451-{[(2S,3S,4R)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 370 0.1 3.71-{[(2S,3S,4S)-4-fluoro-3-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 371 7 6044-(1-methyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 372 11 6494-(1,2-dimethyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 373 35 61624-(2-methyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 374 0.1 1.21-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo(3,4-bisdeutero)pyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6- carboxamide375 0.3 1-{[(2S,3R,4R)-4-fluoro-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide 376 7404-(4-methylpyrimidin-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 377 724-(5-chloropyrimidin-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 378 594-(6-oxo-1,6-dihydropyridin-2-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide 379 5034-(2-methylpyrimidin-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamideIn Vivo Mouse LPS/D-Gal Challenge Model.

Efficacy of IRAK4 compounds of the present invention was also evaluatedin an in vivo mouse model of endotoxin induced (Lipopolysaccharide(LPS)) inflammation. See: S. Copeland, H. W. Warren, S. F. Lowry, S. E.Calvano, and D. Remick, Clin. Diagn. Lab. Immnol. 2005, 12(1), 60-67. Anexemplary protocol for this in vivo model follows.

Female C57/BL6 mice, 8 to 10 weeks old, are orally administered eithervehicle or formulated IRAK-4 compound 1 hour prior to the challenge.Vehicle or IRAK4 compound is administered by oral gavage at a volume of10 mL/kg. One hour post oral delivery of vehicle or compound, theanimals are challenged with an intraperitoneal injection (IP) of asolution containing 1 μg/mL LPS and 80 mg/mL D-gal. Each mouse isinjected with 200 μL of the solution, for a final challenge dose of 100ng LPS and 8 mg D-gal. Ninety minutes post LPS/D-gal challenge, animalsare euthanized and blood collected. Blood is allowed to clot at roomtemperature and serum is separated by centrifugation and stored at −80°C. for analysis. Serum TNF and IL-6 are measured by Meso Scale Discovery(MSD) multiplex platform.

The groups consisted of N=10 animals/group. Naïve animals and vehiclecontrol groups were run with each study. Mean cytokine data was plottedand students T-test was performed to calculate significance (t-test,p<0.05 vs. vehicle) of IRAK4 treated group vs. vehicle treated group.Percent inhibition of cytokine induction was calculated for IRAK4treated group vs. vehicle treated group.

Table 4 contains data from multiple studies with columns for Compound,Dose in mg/kg (mpk) and % inhibition of serum TNF. In cases where dosesof certain compounds were repeated in multiple experiments, the averagepercent inhibition of TNF and standard deviation is shown in the table.

TABLE 4 % Inhibition of TNF in mouse LPS model with various IRAK4inhibitors. Compound Dose (mpk) % inhib TNF Example 26 100 78 (±23) 3041 (±17) 10 27 (±19) Example 173 100 98 30 55 Example 189 30 40 Example194 30 76

Imiquimod Induced Mouse Model of Skin Inflammation.

Efficacy of IRAK4 inhibitors of the present invention was also evaluatedin an in vivo mouse model imiquimod induced skin inflammationinflammation (L. van der Fits, S. Mourits, J. S. A. Voerman, M. Kant, L.Boon, J. D. Laman, F. Cornelissen, A.-M. Mus, E. Florencia, E. P. Prens,and E. Luberts, J. Immunol. 2009, 182, 5836-5845). An exemplary protocolfor this in vivo model follows.

Female Balb/C mice, 12-14 weeks old, received a daily topical dose ofcommercially available imiquimod cream (5%) on the shaved back and theleft ear for 3 consecutive days. This translated into a daily dose of1.56 mg of the active compound. This dosing regimen was optimized toachieve robust skin inflammation in mice as measured by increased earthickness. Vehicle or IRAK4 compounds are administered by oral gavage,twice daily (AM and PM) for 5 consecutive days. Ear thickness weremeasured daily, 1 hour post AM oral administration of compound orvehicle and prior to application of imiquimod. An exemplary protocol forthis in vivo model follows.

-   -   On Day 1, mice were pre-treated with vehicle or IRAK4 inhibitor        by oral gavage at a volume of 10 mL/kg. Oral dosing of compound        or vehicle continued twice daily (BID) for 5 consecutive days.    -   One hour post vehicle or compound delivery, baseline ear        thickness was measured in triplicate using a micrometer        (Mitutoyo) prior to the application of imiquimod. Ear thickness        was measured each day in this manner and then the imiquimod        cream was applied to back skin and left ear on Days 1, 2 and 3.    -   On Day 5 of the study, mice were given the AM dose of vehicle or        IRAK4 inhibitor. One hour after oral delivery, ears were        measured and animals were euthanized. The left ear was        collected; snap frozen and stored at −80° C. for analysis.    -   Data were presented as mean change in ear thickness (microns)        from baseline measurement.    -   Positive control compound for the model was two IP injections of        anti-P40 antibody at a dose of 400 μg/mouse given on Days 1 and        4.

In Vivo Rat Collagen-Induced Arthritis Model.

Efficacy of IRAK4 compounds of the present invention was also evaluatedin a rat in vivo model of rheumatoid arthritis (M. Hegen, J. C. Keith,Jr, M. Collins, C. L. Nickerson-Nutter, Ann. Rheum. Dis. 2008, 67,1505-1515). An exemplary protocol for this in vivo model follows.

Female Lewis rats, approximately 7 weeks old, were immunized with anemulsion of type II collagen (CII) and incomplete Freund's adjuvant(IFA) on day 0 and received a boost of CII/IFA on day 7. Hind paw volumeincrease was taken by plethysmograph. Animals were randomly enrolledinto treatment groups based on the development of disease. Beginning onday 11 post immunization, rats were enrolled into random treatmentgroups based on an increase in a single hind paw volume compared to day7 post immunization baseline measurements.

The groups consisted of: (1) a naive control group, (2) a vehiclecontrol group, (3) a group dosed orally with a p38 inhibitor, (4) apositive control, at 30 mg/kg once a day, (5) a group dosed orally withExample 26 at 100 mg/kg twice a day, (6) a group dosed orally withExample 26 at 30 mg/kg twice a day, and (7) a group dosed orally withExample 26 at 10 mg/kg twice a day.

Ten rats were enrolled per treatment group with the exception of thenaive control group, which contained two rats. Day 0 was designated asthe first treatment day, and paw measurements are taken daily byplethysmograph. The rats were weighed on a daily basis.

IRAK4 inhibitors are efficacious in the Lewis rat model ofcollagen-induced arthritis. Results of the study are presented in FIG. 2which demonstrates the average paw volume increase of the groups dosedorally. In particular, therapeutic treatment BID daily with Example 26for 8 days reduced the hind paw swelling in CIA rats significantly(t-test, p<0.05 vs. vehicle) in the following groups:

Example 26 100 mg/kg PO, BID Day 1-Day 8 (end) Example 26 30 mg/kg PO,BID Day 2-Day 8 BIRB796 30 mg/kg PO, QD Day 1-Day 8

Animals treated with Example 26 at 10 mg/kg PO, BID showed a transientlysignificant reduction in hind paw swelling only on Day 5 and Day 6 posttreatment.

We claim:
 1. A pharmaceutical combination comprising1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide,or a pharmaceutically acceptable salt thereof, and a JAK1 inhibitor, ora pharmaceutically acceptable salt thereof.
 2. A method for treatingrheumatoid arthritis in a human comprising administering to the humanthe pharmaceutical combination according to claim
 1. 3. A pharmaceuticalcombination comprising1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide,or a pharmaceutically acceptable salt thereof, a JAK1 inhibitor, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, vehicle, or diluent.
 4. A method for treatingrheumatoid arthritis in a human comprising administering to the human inneed of rheumatoid arthritis treatment a therapeutically effectiveamount of the pharmaceutical combination according to claim
 3. 5. Apharmaceutical combination comprising1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide,or a pharmaceutically acceptable salt thereof, andN-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide,or a pharmaceutically acceptable salt thereof.
 6. A method for treatingrheumatoid arthritis in a human comprising administering to the humanthe pharmaceutical combination according to claim
 5. 7. A pharmaceuticalcombination comprising1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide,or a pharmaceutically acceptable salt thereof,N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier, vehicle, or diluent, or acombination thereof.
 8. A method for treating rheumatoid arthritis in ahuman comprising administering to the human the pharmaceuticalcombination according to claim 7.